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Nephrogenic Systemic Fibrosis

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  1. 1. Nephrogenic Systemic Fibrosis Chow YW Department of Nephrology, Kuala Lumpur Hospital
  2. 2. <ul><li>Gadolinium Dyes and Nephrogenic Systemic Fibrosis Claims Attorneys Accepting Cases Nationwide </li></ul><ul><li>If you are diagnosed with NSF </li></ul><ul><li>Talk with an attorney in order to protect your legal rights </li></ul><ul><li>Burg Simpson is here to help you </li></ul><ul><li>We take cases on a contingency basis, which means that we are paid only if we bring about a recovery for our clients </li></ul><ul><li>We have already retained national experts in assist us with your case </li></ul>
  3. 3. Nephrogenic Systemic Fibrosis <ul><ul><li>Nephrogenic fibrosing dermopathy </li></ul></ul><ul><ul><li>Fibrosing disorder </li></ul></ul><ul><ul><li>Seen only in patients with renal failure </li></ul></ul><ul><ul><li>Dialysis associated systemic fibrosis </li></ul></ul><ul><ul><li>2 primary features </li></ul></ul><ul><ul><ul><li>Thickening and hardening of skin overlying the extremities and trunk </li></ul></ul></ul><ul><ul><ul><li>Marked expansion and fibrosis of dermis </li></ul></ul></ul><ul><ul><ul><ul><li>A/W CD34+ fibrocytes </li></ul></ul></ul></ul>
  4. 4. Nephrogenic Systemic Fibrosis <ul><li>NFD  NSF </li></ul><ul><ul><li>Fibrosis of muscle, fascia, lungs, heart </li></ul></ul><ul><ul><ul><ul><li>Galan. Curr Opin Rheumato 2006 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cowper. Sem Arthritis Rheu 2006 </li></ul></ul></ul></ul>
  5. 5. Nephrogenic Systemic Fibrosis Epidemiology
  6. 6. Nephrogenic Systemic Fibrosis <ul><li>Exclusively in pt with renal failure </li></ul><ul><li>First discovered – 1997 in HD patients/Tx graft failure </li></ul><ul><ul><li>Initially thought to be scleromyxedema </li></ul></ul><ul><ul><ul><ul><li>Cowper. Lancet 2000 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Hubbard. Br J. Dermatology 2003 </li></ul></ul></ul></ul><ul><li>Patients affected </li></ul><ul><ul><li>PD </li></ul></ul><ul><ul><li>HD </li></ul></ul><ul><ul><li>Transplant recipients </li></ul></ul><ul><ul><li>Advance CKD </li></ul></ul><ul><ul><li>ARF not requiring dialysis </li></ul></ul>
  7. 7. Nephrogenic Systemic Fibrosis <ul><li>215 cases reported till December 2006 </li></ul><ul><ul><ul><li>International NSF Registry, Yale University </li></ul></ul></ul><ul><ul><ul><li>www.icnfdr.org </li></ul></ul></ul><ul><li>Almost all are adults </li></ul><ul><li>No predilection </li></ul><ul><ul><li>Gender </li></ul></ul><ul><ul><li>Race </li></ul></ul><ul><ul><li>Age </li></ul></ul><ul><ul><li>Etiology of kidney disease </li></ul></ul><ul><ul><li>Duration of renal failure </li></ul></ul>
  8. 8. Nephrogenic Systemic Fibrosis Etiology
  9. 9. Nephrogenic Systemic Fibrosis <ul><li>Gadolinium </li></ul><ul><ul><li>Non tissue specific </li></ul></ul><ul><ul><li>Non ionic </li></ul></ul><ul><ul><li>Hyperosmolal (650mosmol/kg) </li></ul></ul><ul><ul><li>Contrast used for MR studies </li></ul></ul><ul><ul><li>Excreted exclusively by the kidneys </li></ul></ul><ul><ul><li>T1/2  1.3 hours (healthy volunteers) </li></ul></ul><ul><ul><li>T1/2  10 hours (GFR 20-40ml/min) </li></ul></ul><ul><ul><li>T1/2  34 hours (ESRD) </li></ul></ul><ul><ul><li>T1/2  2.6 hours if HD done after administration </li></ul></ul>
  10. 10. Nephrogenic Systemic Fibrosis <ul><li>Free Gadolinium (Gd3+) </li></ul><ul><ul><li>Poorly soluble </li></ul></ul><ul><ul><li>Highly toxic </li></ul></ul><ul><ul><li>Can form precipitate with PO4 </li></ul></ul><ul><ul><li>Demonstration of Gad in tissue specimens of pt with NSF </li></ul></ul><ul><ul><ul><ul><li>High WA. J Am Acad Derm 2007 </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Boyd AS. J Am Acad Derm 2007 </li></ul></ul></ul></ul>
  11. 11. NSF- Case Reports <ul><li>Austria (Grobner T. NDT 2006) </li></ul><ul><ul><li>5/9 HD pt developed MRA (3 X dose needed vs MRI) </li></ul></ul><ul><ul><li>Sympt  2-4 weeks after exposure </li></ul></ul><ul><ul><li>No correlation with </li></ul></ul><ul><ul><ul><li>Age </li></ul></ul></ul><ul><ul><ul><li>Sex </li></ul></ul></ul><ul><ul><ul><li>Underlying renal disease </li></ul></ul></ul><ul><ul><ul><li>Drugs therapy </li></ul></ul></ul><ul><ul><ul><li>Dialysis modality </li></ul></ul></ul><ul><ul><ul><li>Co-morbid condition </li></ul></ul></ul>
  12. 12. NSF- Case Reports <ul><li>Denmark (Markmann P. JASN 2006 ) </li></ul><ul><ul><li>13 patient with advance CKD/ESRD </li></ul></ul><ul><ul><li>7- HD, 1-PD, 5- no dialysis </li></ul></ul><ul><ul><li>Sympt  25 days (2-75 days) </li></ul></ul><ul><ul><li>No correlation: Dose and NSF severity </li></ul></ul><ul><ul><li>6/13 had previously been exposed to Gad without problems. </li></ul></ul>
  13. 13. NSF- Case reports <ul><li>FDA </li></ul><ul><ul><li>75 patients </li></ul></ul><ul><ul><li>2days to 18mths before disease onset </li></ul></ul><ul><li>NSF registry </li></ul><ul><ul><li>2-3monts before sympts </li></ul></ul>
  14. 14. RISK ====  5% (advance CKD) Danish Med Agency. 2006
  15. 15. NSF- Possible Associations <ul><li>EPO </li></ul><ul><ul><li>Has fibrogenic properties </li></ul></ul><ul><ul><li>Stimulates bone marrow </li></ul></ul><ul><ul><li>Large number of bone marrow derived CD34+ fibroblast found to infiltrate dermis in NSF </li></ul></ul>
  16. 16. Swaminathan S. Ann Internal Med 2006. <ul><ul><li>22 HD patients with NSF evaluated </li></ul></ul><ul><ul><ul><li>50 control patients (on HD) </li></ul></ul></ul><ul><ul><ul><li>50% of both groups had Gadolinium </li></ul></ul></ul><ul><ul><ul><li>Skin changes occurred after initiation of EPO in all 22 NSF patients </li></ul></ul></ul><ul><ul><ul><li>6/22 patient had EPO dose increase (312u/kg) 1-9months before onset </li></ul></ul></ul><ul><ul><ul><li>NSF patients had higher median EPO dose than controls (427 vs 198 u/kg/wk) </li></ul></ul></ul><ul><ul><ul><li>NSF improved in some patients who stopped or decrease EPO dose </li></ul></ul></ul><ul><ul><ul><li>Data on EPO not as convincing as Gad (95% patients who had NSF had Gad exposure) </li></ul></ul></ul>
  17. 17. Other associations <ul><li>Absence of ACEI </li></ul><ul><li>SSRI, CNI (fibrogenis properties) </li></ul><ul><li>Fistula reconstruction/dialysis catheter placement </li></ul>
  18. 18. Pathology
  19. 19. Pathology <ul><li>Deep biopsy needed (extends to subcutaneous tissue) </li></ul><ul><li>Subtle proliferation of dermal fibrocytes </li></ul><ul><li>Marked thickening of dermis a/w histiocytes and satellite factor XIIIa+ dermal dentritic cells </li></ul><ul><li>Thick collagen bundles with surrounding clefts (prominent findings) </li></ul><ul><li>Variable increase in dermal mucin and elastic fibers on special stains </li></ul><ul><li>Gadolinium- using special stains </li></ul>
  20. 20. Immunohistochemistry <ul><li>Abundant CD34+ dermal cells </li></ul><ul><ul><li>Dendritic cells aligned with elastic fibers and around collagen bundles in dense network </li></ul></ul><ul><ul><li>Also increase CD68+ and factor XIII+ dendritic cells </li></ul></ul>
  21. 21. Sufficiently deep biopsies show increased numbers of fibroblast-like cells in the dermis, extending into the fascia along subcutaneous septa.
  22. 22. The dermis demonstrates haphazardly arranged collagen bundles and a strikingly increased number of spindled and plump fibroblast-like cells
  23. 23. The spindled and plump fibroblast-like cells extend into the fascia along subcutaneous septa.
  24. 24. Mucin is frequently present and demonstrable by the colloidal iron or alcian blue (pH 2.5) staining methods
  25. 25. Small multinucleated histiocytes may also be a feature.
  26. 26. Pathogenesis <ul><li>Not well understood </li></ul><ul><li>Contributors ro exaggerated tissue fibrosis </li></ul><ul><ul><li>Activation of TGF-beta-1 pathway </li></ul></ul><ul><ul><li>Increase in circulating fibrocytes </li></ul></ul>
  27. 27. Clinical Manifestation
  28. 28. Clinical Manifestations <ul><li>Skin involvement in all patients </li></ul><ul><li>Systemic involvement in some patients </li></ul><ul><li>2-4 weeks between exposure and disease onset </li></ul>
  29. 29. Skin involvement <ul><li>Symmetrical </li></ul><ul><li>Bilateral </li></ul><ul><li>Fibrotic </li></ul><ul><li>Indurated papules, plagues, subcutaneous nodules +/- erythematous </li></ul><ul><li>Begins in ankles, lower legs, feet, hands  thigh, forearms, trunk, buttocks </li></ul>
  30. 30. Skin involvement <ul><li>Common distribution patterns </li></ul><ul><ul><li>Involve ankles to below the knees, mid thighs, skin between wrist and mid-upper arms bilaterally </li></ul></ul><ul><li>Unusual distribution patterns </li></ul><ul><ul><li>Mid and lower abdomen </li></ul></ul><ul><li>Head is spared </li></ul><ul><li>Lesions often preceded by edema. Mis Dx as cellulitis </li></ul><ul><li>May have ‘cobble stone’, ‘woody’, ‘peau d orange’ appearance </li></ul><ul><li>May be pruritic +/- sharp pain/burning sensation </li></ul>
  31. 31. Areas of thick, hardened skin, commonly associated with brawny hyperpigmentation, and preferentially localized to the extremities
  32. 32. Extensive thickening of the skin, often associated with brawny hyperpigmentation, and in some cases, distinct papules and subcutaneous nodules.
  33. 33. Systemic Involvement <ul><li>Prevalence unknown </li></ul><ul><li>Muscle induration. Strength normal or slightly reduced </li></ul><ul><li>Joint contractures common in advance disease. </li></ul><ul><li>Reduce ROM d/t periarticular skin thickening </li></ul><ul><li>Fibrosis of fascia </li></ul><ul><li>Lung Fibrosis </li></ul><ul><li>Diaphragmatic fibrosis (resp failure) </li></ul><ul><li>Myorcardium, pericardium, pleura, dura mater </li></ul>
  34. 34. Systemic Involvement <ul><li>Yellow asymp scleral plagues </li></ul><ul><li>Calcification of soft tissue, muscle, vasculature, myocardium, cardiac valves </li></ul>
  35. 35. Diagnosis
  36. 36. Diagnosis <ul><li>Based on HPE </li></ul><ul><ul><li>Deep incisional/punch biopsy </li></ul></ul><ul><li>Investigations </li></ul><ul><ul><li>Elevated ESR/CRP </li></ul></ul><ul><ul><li>-ve connective tissue screen </li></ul></ul><ul><ul><li>Elevated APL A/B </li></ul></ul><ul><ul><li>Depending of organ involvement </li></ul></ul>
  37. 37. Differential Diagnosis <ul><li>Scleroderma </li></ul><ul><ul><li>Raynaud </li></ul></ul><ul><ul><li>ANA, anti centromere, anti DNA topoisomerase I (scl-70) </li></ul></ul><ul><li>Scleromyxedema </li></ul><ul><ul><li>a/w monoclonal gammopathy </li></ul></ul><ul><ul><li>HPE </li></ul></ul><ul><li>Eosinophilic fascitis </li></ul><ul><ul><li>Eosinophilia </li></ul></ul><ul><ul><li>HPE </li></ul></ul>
  38. 38. Course <ul><li>Chronic </li></ul><ul><li>Unremitting </li></ul><ul><li>28%  no improvement </li></ul><ul><li>20%  modest improvement </li></ul><ul><li>28% died </li></ul><ul><li>5%  fulminant course </li></ul><ul><ul><li>Flexion contractures </li></ul></ul><ul><ul><li>Loss of mobility </li></ul></ul><ul><ul><li>Wheelchair bound within weeks </li></ul></ul>
  39. 39. Course <ul><li>Improvement seen mostly in patients with recovered renal function </li></ul><ul><li>Improvement in renal function slows or stops the disease progression </li></ul>
  40. 40. Prevention <ul><li>Gadolinium avoidance </li></ul><ul><ul><li>GFR<30mls/min  5% risk </li></ul></ul><ul><ul><li>GFR 30-60mls/min  no data </li></ul></ul><ul><li>If gadolinium must be given </li></ul><ul><ul><li>Inform patient benefit-risk </li></ul></ul><ul><ul><li>Use Gadobenate dimeglumine (multihance) </li></ul></ul><ul><ul><ul><li>Partially excreted by liver </li></ul></ul></ul><ul><ul><li>Use lowest dose possible </li></ul></ul>
  41. 41. HD patients receiving Gadolinium <ul><li>Gadolinium removal by HD </li></ul><ul><ul><li>1 session  78% </li></ul></ul><ul><ul><li>2 sessions  96% </li></ul></ul><ul><ul><li>3 sessions  99% </li></ul></ul><ul><ul><ul><ul><li>Okada. Acta Radiol 2001 </li></ul></ul></ul></ul><ul><li>ESRD patient on HD </li></ul><ul><ul><li>Schedule MR just b4 HD session </li></ul></ul><ul><ul><li>If not, need additional HD post MR </li></ul></ul><ul><ul><li>Hd to be done ASAP </li></ul></ul>
  42. 42. HD patients receiving Gadolinium <ul><ul><li>Should also do HD the following day if no C/I </li></ul></ul><ul><li>CAPD patients </li></ul><ul><ul><li>Gad clearance  69% after 22 days </li></ul></ul><ul><ul><ul><ul><li>Joffe.Acad Radiol 1998 </li></ul></ul></ul></ul><ul><ul><li>HD after MR </li></ul></ul><ul><ul><li>If cant do HD, IPD cycler 48 hours (no evidence) </li></ul></ul>
  43. 43. CKD patients- GFR <30mls/min <ul><li>Has Fistula? </li></ul><ul><ul><li>HD after MR study </li></ul></ul><ul><li>No fistula </li></ul><ul><ul><li>GFR <15mls/min  temporary CVC and HD (must weigh benefit/risk) </li></ul></ul><ul><ul><li>GFR 15-29mls/min  no need HD </li></ul></ul>
  44. 44. Treatment
  45. 45. Treatment <ul><li>No proven therapy </li></ul><ul><ul><li>Renal transplantation </li></ul></ul><ul><ul><li>Extracorporeal photopheresis (photochemotherapy) </li></ul></ul><ul><ul><ul><li>Exposure of bld to photoactivated 8-methoxypsoralen  reinfusion of treated cells </li></ul></ul></ul><ul><ul><ul><li>ECP induce monocyte derived TNF-alfa  suppresses collagen synthesis, enhances collagenase production </li></ul></ul></ul>
  46. 46. Treatment <ul><li>UV-A phototherapy </li></ul><ul><ul><li>Inhibits procollagen synthesis </li></ul></ul><ul><ul><li>Plasmapheresis </li></ul></ul><ul><ul><li>Pentoxifylline </li></ul></ul><ul><ul><li>IVIG </li></ul></ul><ul><ul><li>Steroids- topical/intralesional/oral </li></ul></ul><ul><ul><li>Cyclophosphamide </li></ul></ul>