Contrast Induced Nephropathy and Nephrogenic Systemic Fibrosis By

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

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

Definition of CIN w Including three components n n n 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 44 umol/l increase of Cr level from baseline Within 48 -72 hrs of exposure Cholesterol embolism, hypotension, UTI etc 3

4

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

• 4622 admitted to medical and surgical ward • 7. 2% with baseline Cr >105 umol/l AJKD, Vol 39, No 5 (May), 2002: pp 930 -936 6

The overall incidence of CIN among general population is around 0. 6 -2. 3% Radiology 1997; 203: 605 -610 7

Pre-existing renal disease % of CIN J Surg Res 1992; 53: 317 -320 8

However… w Serum Cr varies with age, muscle mass and gender -> not reliable enough to identify patients at risk w Use Cockcroft or MDRD equation to calculate Cr. Cl w e. GFR <=60 ml/min/1. 73 m 2 is a reliable cut-off 9

DM + CRF NB: 400 pts, baseline GFR around 50 ml/min Nephrol Dial Transplant 2007, 22, 819 -826 10

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

Anemia Kidney Int 2005; 67: 706 -713 12

Type of CM: Osmolality and Viscosity CM type High osmolar Iothalamate Diatrizoate Low osmolar Iohexol Iopamidol Iopromide Iso-osmolar Iotrolan Iodixanol Osm (mosm) Viscosity (m. Pa*s, 37 C) 1500 >6. 5 500 -700 4. 5 -6. 5 300 1 13

Type of CM Nephrotoxicity of iso-osmolar iodixanol compared with nonionic low-osmolar contrast media: meta-analysis of randomized controlled trials. (25 RCTs) Radiology. 2009 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. 2006 Aug 15; 48(4): 692 -9 Iso-osmolar CM have lower CIN risk c/w low osmolar CM among patients with renal impairment or DM 14

J Am Coll Cardiol 2004, 44, 1393 -99 15

CIN and mortality Mayo Clin Proc. 2008; 83(10): 1095 -1100 16

17

18

19

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

21

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

0. 45% Na. Cl vs 0. 9% Na. Cl N Tx regimen baseline Cr results P NS may be better than 0. 45% Na. Cl 23

Na. HCO 3 vs Na. Cl w 12 RCTs, 1854 patients w Isotonic Na. HCO 3 decrease incidence of CIN (OR 0. 39) c/w Na. Cl w No significant difference in needs for RRT and in-hospital mortality Am J Kidney Dis 2009 Apr; 53 (4), 617 -627 24

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

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

27

NAC beneficial for CIN prevention, especially those with renal impairment Ann Intern Med 2008; 148, 284 -294 28

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

Adenosine antagonist Benefit inconclusive, may be useful Ann Intern Med 2008; 148, 284 -294 30

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

Dopamine and fenoldopam Not useful for CIN prevention Ann Intern Med 2008; 148, 284 -294 32

Lasix Increase risk of CIN Ann Intern Med 2008; 148, 284 -294 33

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

Renal replacement therapy Int J Artif Organs 2008; 31, 515 -524 35

RRT cannot prevent CIN Int J Artif Organs 2008; 31, 515 -524 36

Conclusion w Prevent CIN by n n n Eliminate risk factors if possible Use low or iso-osmolar CM Use lower volume of CM IV hydration (Na. HCO 3 > NS > 0. 45 Na. Cl) NAC 37

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

Peau d’orange skin changes Non-pitting edema with blister and bullae Cobblestoning and induration skin Contracture 39

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

NSF w No single causative agent or trigger was identified previously until 2006 w Five ESRF on HD developed NSF following exposure to Gadolinium-based contrast Nephrol Dial Transplant 21: 1104 -1108, 2006 w Subsequently, numerous published studies and NSF registry have confirmed the link 41

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

Gadolinium based contrast agents available 43

GBCM - pharmacokinetics w w Molecular mass – 500 -1000 Da Distributed in ECF only (0. 26 -0. 28 l/kg) No protein binding Excreted unchanged by kidney, renal clearance approx GFR in normal individual w Half life 1. 3 -1. 6 hrs but prolonged with low GFR 44

GBCM - clearance w Normal t 1/2 1. 3 -1. 6 hr w CKD 3 (30 -59) t 1/2 5 hr w CKD 4 (15 -29) t 1/2 9 hr w CKD 5 (<15) t 1/2 34 hr w HD t 1/2 2. 1 hr w PD without residual renal fx t 1/2 53 hr 45

NSF - Pathogenesis w Delay in GBCM excretion due to renal impairment w Spontaneous dissociation of the Gd-chelate complex into metal-ion and ligand w Free Gd forms precipitate with anions (PO 4, CO 3 etc) in the tissue w Internalized macrophages w Produce cytokines w Attract circulating fibrocytes w Induce tissue fibrosis 46

47

48

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 photoirradiated cells are washed free of the drug and re-infused into the patient. Indications: Cutaneous TCL, scleroderma 49

End of presentation Questions and Comments 50