1. Nephrogenic systemic fibrosis
이상헌

2. Nephrogenic systemic fibrosis (NSF)
Introduction
Nephrogenic systemic fibrosis (NSF)
Thickening and hardening of the skin overlying the extremities and trunk
Marked expansion and fibrosis of the dermis with CD34-positive fibrocytes
Not only skin involve
Fibrosis of deeper structure : muscle, fascia, lung, heart
Nephrogenic fibrosing dermopathy  NSF

3. Nephrogenic systemic fibrosis (NSF)
Epidemiology
Nephrogenic systemic fibrosis (NSF)
1st case  1997~2000, HD & failed KT patients, severe skin induration
 scleromyxedema in HD ?
Jan, 2013, International NSF Registry at Yale University (>400 case )
No predilection (gender, race, age, duration of renal failure…)
PD patients  higher risk than HD
Case-control study, 4yr : 4.6case in PD VS case in HD (7.5 times)
(CDC, MMWR Morb Mortal Wkly Rep, 2007;56:137)

4. Etiology
Gadolinium
Non-radioactive, paramagnetic (lanthanide), similar size with Ca 2+
Non-tissue specific, hyper-osmolar (650mosmol/kg)
Toxicity  Gd3+ bound to proprietary ligand(chelate)
Chelate reduce interaction with tissue, facilitate their excretion
(ionic or non-ionic, linear or cyclical)
Ionic & cyclic chelate : bind Gd more strongly  less toxic
Linear chelate : gadopentetate(Magnevist), gadodiamide(Omniscan), gadobenate(MultiHance) , gadoversetamide(OptiMARK)
Macrocyclic chelate : gadoteridol(ProHance)  greater thermodynamic stability

5. Gadolinium Etiology Excret almost by kidney
Heathy (half-life 1.3hr), eGFR(20-40)  10hr, ESRD  34hr
ESRD on HD  half life become 1.9~2.6hr

6. Etiology
Gadolinium
FDA, Black box warning, gadolinium based agent in 2007
NSF is greater with linear (ex. Gadodiamide , 80% of NSF in US)
FDA, Black box warning, 2010  Not advertizing Omniscan, OptiMARK, Magnevist
in patient with AKI or CKD with eGFR<30ml/min
2.5~5% in 400~500 dialysis patients
AKI (eGFR 15~59) patient (Am J Roentgenol, 2007;188:58)
Dose dependent ! : double dose  odd ratio 22.3 (Am J Roentgenol, 2007;188:58)

7. 2 proposed contributor Pathogenesis TGF-beta-1 Circulating fibrocyte ↑
TGF-beta-1 mRNA level ↑ in skin & fascia
CD68+/factor XIIIa+ dendritic cell ↑
Noxious stimulus  activate CD68+/factor XIIIa+ dendritic cell  produce
TGF-beta-1  recruit & activate dendritic cell  tissue fibrosis
Circulating fibrocyte ↑
Putative toxin stimulate BM  produce CD34+ circulating fibrocyte 
accumulate in tissue  produce collagen

8. Role of free Gd 3+ Pathogenesis
Free Gd : poorly soluble, highly toxic, precipitate with anion
Precipitate in tissue  disrupt Ca 2+ ion passage in nerve & muscle
Disrupt transmetallation : endogenous metal (zinc & copper)

9. Clinical manifestation
Latent period : usually 2~4 weeks, 2 days ~ 18 months
Skin involve
Symmetrical, bilateral indurated papule, nodule
1st involve  ankle, lower leg, feet, hand  move proximally
 thigh, forearm, trunk, buttock, head is spared
Thickened & firm texture : peau d’ orange (orange peel-like)
Pruritic, buring sensation
Joint movement limitation

10. Clinical manifestation
Systemic involvement
Muscle induration, strength is normal or slightly reduced
Joint contracture, synovitis(-) & arthritis(-)
Lung : reduced diffusion capacity, diaphragm : respiratory failure

11. Deep incisional or punch biopsy
Diagnosis
Deep incisional or punch biopsy
Fribrotic lesion extend to SQ tissue
Immunohistochemical stain : abundant CD34+ dermal dendritic cell

18. Scleroderma, scleromyxedema, eosinophilic fascitis
DDX
Scleroderma, scleromyxedema, eosinophilic fascitis
ANA, Anti-centromere, Anti-DNA topoisomerase I (Scl-70) Ab
Scleromyxedema : monoclonal gammopathy (Ig G lambda)
Eosinophilia : not in NSF

19. Prevention
Avoid of Gd
US FDA : eGFR <30 & Dialysis, eGFR<30 & AKI  should avoid !
Omiscan, OptiMARK, Magnevist should be avoided
American College of Radiology : eGFR 30~40  Avoid !
Prompt HD after Gd imaging study (although there are no data)

20. If Gd must be given !! Prevention Avoid linear chelate
2012 KDIGO  Use macrocyclic chelate (gadoteridol, gadobutrol)
Lowest dose
HD immediately !! (within hours, not day)
70 HD patients with Gd  1st HD (78%) 2nd HD(96%) 3rd HD(99%)
(Okada S. et al. Acta Radiol 2001;42:339)
13 anuric patients, elimination of gadodiamide, at 1~4.5hr after exposure
 1st HD(73%) 2nd (93%) 3rd (99%) (Saitoh T et al. Radiat Med 2006;24:445)

21. Treatment
No proven medical Tx. KT

22. Treatment
Imatinib
57yr, white women c HD, MRI c Gd 3 times for cancer work-up
Mar 2006, NSF is diagnosed
Jun 2006, imatinib 400mg daily  improvement in the swelling and decrease in plaques of the lower extremities (after 4 weeks)
300mg twice  increased mobility, decreased pain, and resolution of the edema and induration

23. Treatment

25. Case
김OO
C.C : Lt. AVF infection (2009/8/19 GS 입원, 10/22 MI 전과)
Brief Hx
57세 여자 환자 2009년 8월 19일 Lt.AVF infection으로 본원 GS 입원.
09/8/25 Graft remove 시행 후 Fever 지속
09/8/27 Hip & SI joint MRI c enhance (d/t Lt. hip pain)
09/9/2 AP-CT: Abscess on Lt.posas m. & illiacus muscle and erector spinae muscle
09/9/4 I & D (E.coli) 시행하였고 이후 지속적으로 CT F/U 하였고 Ciprofloxacin 사용
09/9/19경부터 양측 상지와 하지에 motor & Sensory 떨어져 신경과 협진하였고
severe sensorimotor polyneuropathy 진단 하에 보존적인 치료 중이었음. (Prof.김태형/R3이상헌)

26. Gd ? Always check! Case Problem list #1. HTN (13년전)
#2. ESRD on HD (월수금, 09/10/12 Rt. perm femoral catheter)
#3. Infected AVG -> 09/8/19 Admission GS, 09/8/25 remove
#4. S/p E. coli BSI
#5. Gastric & Duodenal ulcer
#6. Lt. hip septic arthritis, OM (2009/8/27 L-spine MRI)
#7. Lt. psoas m. abscess, Both gluteus m. abscess (2009/8/27 L-spine MRI)
d/t #4 (09/9/4 I & D, culture -> E.coli)
#8. Ischemic colitis
#9. Suspect Vertebral Osteomyelitis (T9-T11)
#10. Severe sensorimotor polyneuropathy (09/9/22 NCV)
#11. Adrenal insufficiency & Hypothyroidism
Gd ?
Always check!

27. Case
2009/12/17 Punch biopsy

28. 본원에서 사용 중인 Gadolinium Gadolinium
Dotatrem® Gadovist ® ProHance® Primovist ®
Primovist : linear chelate, higher protein binding capacity
<Liver dynamic MRI>
ESRD on HD  liver dynamic MRI c Gd시행하면 바로 투석!!