1. Nephrogenic Systemic Fibrosis 高雄長庚腎臟科 Fellow 2 王奕淳 VS 莊峰榮 & Chief 李建德 2009.10.14 Kidney forum

2. Question 什麼是 NSF? Gadolinium 會導致 NSF 嗎 ? 腎功能多差時要避免 Gadolinium? Gadolinium 需要預防性洗腎 ?

3. Q: 什麼是 NSF?

4. NSF: Clinical Patients with renal insufficiency Swelling of distal parts of the extremities Subsequent thickening, indurations and hardening of the skin Distinct nodules Kidney International (2007) 72, 260–264

5. NSF: Clinical The distal extremities are the most common area of involvement Followed by the trunk. The face is almost never involved. Kidney International (2007) 72, 260–264

6. Diffuse thickening, induration, and hyperpigmentation of lower legs with inhibition ofjoint flexion.

7. Diffuse swelling of the skin, erythematous papules and nodules

8. NSF :Skin biopsy Thickened dermis Bundles of collagen Surrounding clefts Mucin deposition Proliferation of fibroblasts Proliferation of elastic fibers No inflammation Kidney International (2007) 72, 260–264

9. The dermis is thickened and demonstrates swollen collagen bundles with surrounding clefts and spindle cell proliferation. Interstitial mucin deposition is frequently present

10. Fibrocytes (yellow arrow) and swollen collagen bundles (green arrow) with surrounding clefts are shown. Interstitial mucin (red arrows) is increased The light blue arrow indicates degenerated collagen fibers

11. Q: Gadolinium 會導致 NSF 嗎 ?

12. NSF: History 1997: Recognition NSF 2000: First description in literature 2006: (NDT) 5 patients received MRI and subsequently developed NSF within 2–4 weeks. 2006 (JASN) 13 patients acquire NSF when exposed to gadodiamide (OR 32.5) 2007 FDA Warning Kidney International (2007) 72, 260–264

13. FDA Warning [Posted 05/23/2007] Risk for NSF following exposure to GBCA Acute or chronic severe renal insufficiency (GFR <30 mL/min/1.73m2) Acute renal insufficiency of any severity Hepato-renal syndrome Peri-operative liver transplantation period.

14. FDA Warning Healthcare professionals should avoid the use of a GBCA in these patients Unless diagnostic information is essential and not available with non- contrast enhanced MRI

15. Radiology: Volume 245: Number 1—October 2007 A retrospective analysis was performed of all adult patients undergoing dialysis in the west of Scotland between January1, 2000, and July 1, 2006

16. Patient All patients who underwent renal replacement therapy (RRT) for established chronic renal failure (stage 5 chronic kidney disease, estimated GFR <15 mL/min)

17. Results 14 of 1826 patients had NSF 13/14 (93%) undergone gadolinium enhanced MRI 408/1812 (22.5%) unaffected (P <001)

18. Conclusion The data support a positive association between gadolinium based contrast agent administration and development of nephrogenic systemic fibrosis in the established renal failure population

22. The odds of developing NSF were 27 times greater in patients exposed to gadolinium

23. The odds of developing NSF were 20 times greater in patients exposed to gadodiamide

24. Conclusion The current state of evidence suggests an association and potentially causal link between the use of GBCAs and the development of NSF among patients with advanced kidney disease

25. Q: 腎功能多差時要避免 Gadolinium?

26. Gadolinium PatientHalf life Healthy volunteers1.3 hr Chronic renal failure30–120 hr Hemodialysis2.6 hr Peritoneal dialysis52.7 hr Kidney International (2007) 72, 260–264

27. NSF in CKD Prevalence of NSF Stage 1–4 CKD: 0% Stage 5 CKD of 18% Invest Radiol 2008; 43: 141–144

28. NSF in CKD NSF has been observed in up to 18% of patients receiving chronic haemodialysis May occur in individuals with stages 3 and 4 chronic kidney disease Occasionally in individuals who had experienced acute renal failure Ann Rheum Dis 2008;67(Suppl III):iii66–iii69.

29. American College of Radiology (ACR) In patients with stage 3 or moderate CKD, the ACR noted that there were insufficient data to make any recommendations Cleve ClinJ Med 2008; 75: 95 – 97

30. FDA & ACR FDA and the ACR both recommend Withholding all GBCAs in CKD stage 4–5 (GFR<30 mL/min/1.73m2) Kidney International (2007) 72, 260–264

31. The journal of urology 180, 830-835, September 2008

32. Kidney International (2009) 75, 465–474 Safety studies, including USPIO administration (ferumoxytol) as iron supplement therapy in CKD patients on and not on dialysis, suggest that decreased kidney functiondoes not alter the safety profile.

34. Q: Gadolinium 需要預防 性洗腎 ?

35. Prophylactic HD for NSF Three patients have been described who developed NSF developed despite daily hemodialysis for 3 days immediately following gadodiamide exposure Am J Roentgenol 2007;188(2):586–592.

36. Prophylactic HD for NSF Patients who received hemodialysis within 24 hours still developed NSF. Absence of controls, investigators could not ascertain whether the risk and severity of the NSF was reduced. Hemodialysis was not started until at least 9 hours postexposure. Fundam Clin Pharmacol. 2006;20:563-576.

37. Radiologist’s view If there is no alternative to the use of gadodiamide The lowest diagnostic dose should be used Prompt dialysis after imaging may facilitate removal of gadodiamide Radiology: Volume 245: Number 1—October 2007

38. FDA’s view If patients with severe CKD need GBCAs Prompt haemodialysis following contrast administration should be considered http://www.fda.gov/CDER/drug/Inf oSheets/HCP/gcca 00612HCP.htm

39. ACR’s view Prophylactic use of dialysis be warranted only in patients who were already on dialysis. For patients not already on haemodialysis (e.g. stage 3 or 4 CKD) =>The risks of initiating haemodialysis should be weighed against that of developing NSF Am J Roentgenol 2007; 188: 1447–1474

40. Question Gadolinium 會導致 NSF 嗎 ? =>Yes! 腎功能多差時要避免 Gadolinium? =>Stage 4-5 (FDA) Gadolinium 需要預防性洗腎 ? =>Stage 5!, Stage 3-4?(ACR)

41. Conclusion Potentially causal link between GBCAs and development of NSF among patients with advanced kidney disease Withholding all GBCAs in CKD stage 4–5 (GFR<30 mL/min/1.73m2) USPIOs such as ferumoxytol as an alternative to GBCA in patients at risk for NSF Prophylactic use of dialysis after GBCAs in patients who were already on dialysis

42. Thanks for your attention!