1. Contrast Induced Nephropathy and Nephrogenic Systemic Fibrosis
By Dr. HP Shum
Apr 2008

2. Overview Contrast induced nephropathy (CIN)
Definition
Pathogenesis
Prevalence
Risk factors
Adverse outcome
Prevention
Nephrogenic systemic fibrosis

3. Definition of CIN Including three components
Absolute or relative increase in serum Cr compared to baseline
Temporal relationship between the rise of Cr and exposure to contrast agents
Exclusion of alternative explanations for renal impairment
>25% or 44umol/l increase of Cr level from baseline
Within hrs of exposure
Cholesterol embolism, hypotension, UTI etc

4. Correlate with RIFLE “risk” category or AKIN “AKIN 1” category…

5. Pathogenesis Use of adenosine antagonist Use of IVF / IOCM Use of IOCM
Use of NAC
Use of IVF / IOCM

6. 4622 admitted to medical and surgical ward
7.2% with baseline Cr >105umol/l
This study look for prevalence of hospital acquired renal impairment.
Imaging studies are essential part of pt’s mx and the risk of contrast nephropathy should not be under estimated…
AJKD, Vol 39, No 5 (May), 2002: pp

7. The overall incidence of CIN among general population is around 0. 6-2
Radiology 1997; 203:
The overall incidence … but some patients have particularly high risk for CIN. This table indicate the risk factor…

8. Pre-existing renal disease
% of CIN
J Surg Res 1992; 53:

9. However…
Serum Cr varies with age, muscle mass and gender -> not reliable enough to identify patients at risk
Use Cockcroft or MDRD equation to calculate CrCl
eGFR <=60ml/min/1.73m2 is a reliable cut-off

10. DM + CRF NB: 400 pts, baseline GFR around 50ml/min
Around 400 patients, baseline GFR around 50ml/min, compare risk of CIN in those DM, pre DM (IGT) and normal glucose level pts
Nephrol Dial Transplant 2007, 22,
NB: 400 pts, baseline GFR around 50ml/min

11. Volume of CM DM patients receiving PCI Am J Cardiol 2004; 94:300-305

12. Anemia
Kidney Int 2005; 67:

13. Type of CM: Osmolality and Viscosity
CM type
Osm (mosm)
Viscosity
(mPa*s, 37C)
High osmolar
Iothalamate
Diatrizoate
1500
>6.5
Low osmolar
Iohexol
Iopamidol
Iopromide
Iso-osmolar
Iotrolan
Iodixanol
300 1
High and low osmolar CM are both ionic and iso-osmolar CM is non-ionic. High osmolar CM use upto late 1980…

14. Type of CM
Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials. (25 RCTs)
Radiology Jan;250(1):68-86
A meta-analysis of the renal safety of isosmolar iodixanol compared with low-osmolar contrast media. (26 RCTs)
J Am Coll Cardiol Aug 15;48(4):692-9
>3000 and >2000 pt meta-analysis concluded that …
Iso-osmolar CM have lower CIN risk c/w low osmolar CM among patients with renal impairment or DM

15. CIN risk score to predict potential risk of CIN
J Am Coll Cardiol 2004, 44,

16. CIN and mortality Mayo Clin Proc. 2008;83(10):1095-1100
Why the presence of CIN so important
Patients undergone any types of contrast study
Mayo Clin Proc. 2008;83(10):

20. CIN Consensus Working Panel Am J Cardiol 2006;98:2K-4K

22. IV Hydration Decrease activity of the RAAS
Reduce vasocontrictive hormones like endothelin
Increase sodium diuresis
Decrease tubulo-glomerular feedback
Prevent tubular obstruction
Protect against reactive oxygen species
Dilute contrast medium in tubules

23. NS may be better than 0.45% NaCl
0.45% NaCl vs 0.9% NaCl
N Tx regimen baseline Cr results P
NS may be better than 0.45% NaCl

24. NaHCO3 vs NaCl 12 RCTs, 1854 patients
Isotonic NaHCO3 decrease incidence of CIN (OR 0.39) c/w NaCl
No significant difference in needs for RRT and in-hospital mortality
Am J Kidney Dis 2009 Apr; 53 (4),

25. Oral vs IVF Inconclusive, IVF may be better than oral route

26. NAC Potent anti-oxidant
Scavenger of wide variety of oxygen derived free radicals
Prevent direct oxidative tissue damage

28. Involving 26 RCT, more than 3000 patients. Recommand 1
Involving 26 RCT, more than 3000 patients. Recommand 1.2g bd the day before and the day of procedure
NAC beneficial for CIN prevention, especially those with renal impairment
Ann Intern Med 2008; 148,

29. Adenosine antagonist (amiophylline and theophylline)
CM bind to renal adenosine receptor
Causing potent vasoconstriction
Impair renal blood flow
Adenosine antagonist may reverse renal vasoconstriction

30. Adenosine antagonist Benefit inconclusive, may be useful
May be beneficial and further study needed
Benefit inconclusive, may be useful
Ann Intern Med 2008; 148,

31. Dopamine and fenoldopam
Induce renal vasodilatation
Increase renal blood flow
Increase urine output

32. Dopamine and fenoldopam
Not useful for CIN prevention
Ann Intern Med 2008; 148,

33. Lasix
Increase risk of CIN
Ann Intern Med 2008; 148,

34. Renal replacement therapy
CM properties
Water solubility
Low protein binding
Low intracellular penetration
“middle size” molecules, much larger than urea and creatinine
80% removal over 4hrs time by high flux dialyzer but much lower for low flux membranes
PD also remove CM but much slower (50% removal over 16 hrs)

35. Renal replacement therapy
Int J Artif Organs 2008; 31,

36. RRT cannot prevent CIN
Int J Artif Organs 2008; 31,

37. Conclusion Prevent CIN by Eliminate risk factors if possible
Use low or iso-osmolar CM
Use lower volume of CM
IV hydration (NaHCO3 > NS > 0.45 NaCl)
NAC

38. Nephrogenic Systemic Fibrosis
Scleroderma-like systemic fibrosing disorder
Originally termed “nephrogenic fibrosing dermopathy” due to its dominant skin findings but subsequently changed to NSF because of its systemic involvement
First case description in 1997

39. Peau d’orange skin changes
Non-pitting edema with blister and bullae
Rapid onset of dermatological condition, pain contracture, strongly affecting functional status
Contracture
Cobblestoning and induration skin

40. Collagen bundles in thickened reticular dermis
Extend through subcutaneous tissue
Often involve fascia and skeletal muscle

41. NSF
No single causative agent or trigger was identified previously until 2006
Five ESRF on HD developed NSF following exposure to Gadolinium-based contrast
Nephrol Dial Transplant 21: ,2006
Subsequently, numerous published studies and NSF registry have confirmed the link

42. Gadolinium Silvery white rare earth metal
Strongly paramagnetic at room temp
Solution of organic gadolinium complex are used as MRI contrast

43. Gadolinium based contrast agents available

44. GBCM - pharmacokinetics
Molecular mass – Da
Distributed in ECF only ( l/kg)
No protein binding
Excreted unchanged by kidney, renal clearance approx GFR in normal individual
Half life hrs but prolonged with low GFR

45. GBCM - clearance Normal t1/2 1.3-1.6hr CKD 3 (30-59) t1/2 5hr
HD t1/2 2.1hr
PD without residual renal fx t1/2 53hr

46. NSF - Pathogenesis Delay in GBCM excretion due to renal impairment
Spontaneous dissociation of the Gd-chelate complex into metal-ion and ligand
Free Gd forms precipitate with anions (PO4, CO3 etc) in the tissue
Internalized macrophages
Produce cytokines
Attract circulating fibrocytes
Induce tissue fibrosis

49. Procedure in which 10-15% of the patient's white blood cells are removed from the body by leukapheresis. White blood cells are exposed to a chemical agent that is activated by ultraviolet A (UVA) light. Activation by the UVA light induces an inhibition of the host response to foreign histocompatibility antigens. The photo-irradiated cells are washed free of the drug and re-infused into the patient.
Indications: Cutaneous TCL, scleroderma

50. End of presentation Questions and Comments