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Contrast Induced Acute Kidney Injury

Contrast Induced Acute Kidney Injury. Cardiology Catheterization Conference 4/14/2011 Peter Danyi MD. The scope. Pubmed search Contrast induced nephropathy-4671 718 reviews First report 1955, Alwall et al. Acta Med Scand. Definition.

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Contrast Induced Acute Kidney Injury

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  1. Contrast Induced Acute Kidney Injury Cardiology Catheterization Conference 4/14/2011 Peter Danyi MD

  2. The scope • Pubmed search • Contrast induced nephropathy-4671 • 718 reviews • First report 1955, Alwall et al. Acta Med Scand

  3. Definition • An increase in serum creatinine generally occuring within 24hrs, peaking up to 5 days after, and returning to baseline within 3 weeks. • Definition varies, increase in Cr of >25-50% from baseline and/or >0.5-1.0 mg/dL after 48-72 hrs. • European Society of Urogenital Radiology 25% or 0.5 mg/dl • Second International Consensus Conference of the Acute Dialysis Quality Initiative – defines renal failure in terms of GFR and urine output.

  4. Epidemiology CIN Consensus Working panel report 2006 • First reports over 50 years ago • Common and potenitally serious complication following administration of constrast media (CM) in patients with risk for acute renal injury • Incidence reports varies widely depending on patient population and baseline risk factors

  5. Definition and frequency of CIN The frequency of contrast-induced nephropathy depends on the definition used. N 1,826 patients undergoing percutaneous coronary intervention. (Adapted from Am J Med3 and J Invasive Cardiol.4)

  6. Definition in number of trials Numbers of trials in the literature using the following definitions of contrast-induced nephropathy: 0.5 mg/dL (44.2 mol/L) increase, 1.0 mg/dL (88.4 mol/L) increase, 25% increase, and 50% increase.

  7. Incidence • Large scale studies in general hospital patients provide best estimate of healthcare impact • CIN has decreased over the past decade from ~15% to ~7% recently • Nash et al. 4622 patients, 7.2% CIN • Thought to be due to • Greater awareness of the problem • Better risk prevention measures • Improved iodinated contrast media • Total number of cases did not decline due to increasing number of procedures requiring contrast

  8. Impact • Radiographic contrast media is the third most common cause of hospital acquired renal failure (after decreased renal perfusion and nephrotoxic medications), accounting for 11% of cases • In-hospital mortality rate of CIN as high as 14%1 • In patients with multiple risk factors, incidence of CIN can rise to 50% or great er2 • Differential diagnosis: cholesterol embolism-can be difficult to distinguish, but typically occurs over 3-8 weeks, in elderly men, may have cutaneous signs 1 Nash et al. Am J Kidney Dis 2002 2 McCullough PA et al. Am J Cardiol 2006

  9. Mortality risk • Levy et al., 1996, retrospective study of >16,000 patients with 2% CIN incidence, but 34% vs. 7% risk of death for CIN • After adjustment the odds of dying was 5.5 for patient with CIN • Rihal et al., 2002, retrospective study of 7,586 patients noted a CIN incidence of 3.3% and a 22% vs. 1.4% in-hospital mortality for patients with CIN • McCullough et al., 1997 reported a mortality rate of 7.1% for CIN, 35.7% if patient required HD, vs. 1.1% for no CIN. 2 year mortality was 81.2% for HD patients • Significant association was found between >25% Cr increase and one year mortality (Gruberg et al, 2000)

  10. Creatinine rise and1-year mortality Depiction of 1-year mortality rates according to postprocedure increase in serum creatinine J Am Coll Cardiol

  11. Clinical course and outcome • CIN is associated with late cardiovascular events • Lindsay et al. 2003: 5,967 patients, post PCI registry showed AMI 24% vs. 11.6%; TVR at 1 year 28.8% vs. 20.3% • Lindsay et al. 2004: CIN is associated with CKMB rise, CIN and CKMB rise together has 26% 1 year risk for death or MI • Higher incidence of in-hospital events with CIN • CABG • Bleeding requiring transfusion • Vascular complications • Longer hospital stay • Gruberg et al. did not find increased MI or revascularization rates

  12. Economic impact • Subramanian et al. in 2007 published an economic analysis in J. Med. Econ. of CIN • Average additional cost was $10,345 for the hospital stay and $11,812 to 1 year • Incidence and outcome data was determined through systematic literature search • The major driver for the cost was increased hospital stay

  13. Pathophysiology • Poorly understood, complex syndrome, little known about underlying cellular mechanism • Available contrast media constitute diverse family (ionic, nonionic, high/low/iso-osmolar) • Biphasic response or immediate vasoconstriction (dose dependent) and reduction of renal blood flow (up to 50%, lasting for hours) • Subsequent stasis of contrast causes • direct tubular injury and death (osmotic nephrosis-intense focal or diffuse vacuolization of the proximal tubules- or overt tubular necrosis)) • vasoconstriction through Ca influx causing regional cortico-medullary and outer medullary blood flow reduction

  14. Pathophysiology • Endothelins (if contrast >150 ml), adenosine (prolonged vasoconstriction, A1 receptors) and angiotensin II released causing vasoconstriction • Nitric oxid production reduced (in proportion to osmolality of agent), reactive oxygen species production (due to hypoperfusion) increased • Iron plays a role in oxidative injury in CIN - ? role of iron chelation therapy

  15. Pathophysiology • Chronic Kidney Disease (CKD) predisposes to the development of contrast-induced acute kidney injury (AKI). Contrast-induced AKI assumes baseline reduced nephron number with superimposed acute vasoconstriction • Any superimposed insult such as sustained hypotension, microshowers of atheroembolic material from catheter exchanges, use of IABP, or a bleeding complication can amplify the injury processes occurring in the kidney

  16. Factors involved in CIN pathogenesis

  17. Postulated Pathophysiology of CIN In the presence of a reduced nephron mass, the remaining nephrons are vulnerable to injury. Iodinated contrast, after causing a brief (minutes) period of vasodilation, causes sustained (hours to days) intrarenal vasoconstriction and ischemic injury. The ischemic injury sets off a cascade of events largely driven by oxidative injury causing death of renal tubular cells. If a sufficient mass of nephron units are affected, then a recognizable rise in serum creatinine will occur

  18. Risk factors

  19. Other risk factors • Increasing age • Gender data inconsistent • Earlier studies reported higher incidence in nonwhites (Lindsay, 2003) and African Americans (Dangas, 2005) but these findings have not been replicated • Intraarterial administration and osmolality and volume of contrast • The effect of risk factors is additive. If a patient has 4 or 5 risk factors, risk of CIN is 50%

  20. Risk models McCullough et al. Am J Cardiol 2006

  21. CIN Mehran Risk Score . Mehran et al. JACC 2004

  22. Risk reduction strategies • Contrast • IVF • NaHCO3 • N-Acetylcysteine • Ascorbic acid • Statin • ACEi • Theophyllin/aminophylline • Diuresis • Dopamine/Fenoldopam • Prostaglandin/prostacyclin • ANP • Mechanical (HD, hemofiltration, RenalGuard)

  23. Contrast • First contrast agent described in CIN was iodopyracet, a di-iodinated pyridine derivative. That class was replaced by tri-iodinated benzoic acid derivatives and later high osmolar contrast media (HOCM), 2000 mOsm/kg • HOCM is upto 8 times the plasma osmolality, includes: • Diatrozate, Metrizoate, Ioxithalamate, Iothalamate • Osmolality can be reduced by less iodine in the molecule or using nonionic agents (LOCM), 6-800 mOsm/kg. Nonionic monomers: iohexol (Omnipaque), iopamidol, iopentol, iomeprol, iobitridol, ioversol. Dimer: ioxaglate • Iso-osmolar nonionic dimer, 290 mOsm/kg: iodixanol (visipaque)

  24. Contrast • 31 studies evaluate HOCM vs LOCM, pooled data shows LOCM associated with significantly less CIN, pooled OR 0.61 (0.48-0.77) • Comparison of LOCM-s: small studies, no significant difference overall. 64% of patients had some increase in Cr • IOCM (iodixanol) and LOCM have been compared, all in 2009: • Wessely et al. (N=324) did not found a difference (iomeprol) • Chuang et al (N=50) did not found a difference (iohexol) • Mehran et al. ICON study (N=146) nonsignificant difference (ioxaglate) • Laskey et al. (418 DM pts) no difference (iopamidol-Isovue)

  25. Contrast • LOCM vs. IOCM- meta-analysis of 16 studies with 2763 patients • No difference when IOCM compared to LOCM collectively • Iodixanol (IOCM) had lower incidence of CIN when compared to ioxaglate and iohexol (Omnipaque) separately • No difference when compared to other agents

  26. Contrast • Contrast volume is independent predictor for CIN, although not all studies have shown that. The worse the CKD is, the lower amount of contrast can cause CIN. • CIN consensus panel: >100 ml of contrast is associated with higher incidence of CIN, but there is no threshold amount • Intra-arterial administration is associated with higher rate of CIN and LOCM is more beneficial over HOCM than with intravenous use

  27. Statins • Pleiotropic effect of antioxidative and anti-inflammatory properties • Systematic review (Xhang, Am J Nephrol, 2011) found 6 cohort studies and 6 RCTs. Heterogeneity found among studies. • 4/6 cohort studies found chronic statin therapy beneficial • Most RCTs failed to show benefit. • Chronic statin therapy may be more beneficial than only around fhe time of CM administration • Dose of beneficial statin uncertain

  28. Statins Zhang et al. Am J Nephrol. 2011

  29. Statins Zhang et al. Am J Nephrol. 2011

  30. Statins-RCTs

  31. N-Acetylcysteine • Scavanges ROS, reduces the depletion of glutathione, stimulate vasodilatory mediator release (incl. nitric oxid) • Tepel et al. (NEJM 2000) first described its efficacy in preventing CIN • Since then a multitude of trials published with highly conflicting results (largest trial 487 patients) • A number of meta-analysis published • Kelly et al. analyzed 26 trials, 3393 pts, RR=0.62 (0.44-0.88) • Gonzales et al. 22 trials, 2746 pts, found two clusters- one NAC was protective, Cr decreased-NAC not actually effective, but rather an artifactual Cr decrease not due to NAC • Trivedi et al. analyzed high dose NAC only, OR=0.46 (0.33-0.63)

  32. N-Acetylcysteine

  33. N-Acetylcysteine Kelly et al. Ann Int Med 2008;148:284-94

  34. IV Fluids • IVF protects against CIN in two ways • Intravascular space expansion blunts the vasoconstrictive effect of contrast in the medulla by suppressing vasopressin, RAAS, increasing prostaglandins • Attenuates direct toxic effect of contrast on tubules by decreasing concentration and viscosity • Solomon et al (1994 NEJM) published that 0.45% NS was more effective in preventing CIN than IV mannitol or furosemide (11% vs 28% vs 40%) • Trivedi et al (Nephron 2003) confirmed that IVF itself was beneficial (CIN 3.7% for 0.9% NS vs. 34.6% unrestricted oral fluids) • The effect of tonicity of IVF was evaluated by Mueller et al. (Arch Int Med 2002) low risk pts randomized to 0.45 vs 0.9 NS. (CIN was 2% vs. 0.9%)

  35. IV fluids • More recently isotonic normal saline vs sodium bicarbonate has been the focus of investigation • The generation of ROS thought to be mitigated by NaHCO3 • 10 clinical trials in the past 5 years (largest trial 502 patients) • 6 had lower incidence of CIN in the NaHCO3 group, 4 showed no significant benefits • 11 meta-analysis published • Zoungas et al. (Ann Int Med 2009) 23 pooled studies RR 0.62 (0.45-0.86), but found significant publication bias, unpublished trials did not show benefit • Kunadian et al. (Eur J Radiol 2010) found the same

  36. NaHCO3 vs. NaCl Weisbord, Pavelsky. Curr Opin Nephrol Hypertens. 2010

  37. Atrial natriuretic peptid • Morikawa et al (JACC 2009) single center RCT ANP+IVF or IVF alone cath+/-PCI • ANP at 0.042 mcg/kg/min 4-6 hrs prior and 48 hrs past • eGFR at 24, 48 hrs, 1 week and 1 month • Slight benefit of ANP in Cr, no benefit in HD/hosp. rate • Prior studies were negative, but this on had lower ANP dose for longer time • No conclusive evidence yet, would need larger trials

  38. Prostoglandin/prostacyclin analogs • PGI2, PGE2 have renal vasodilatory effects (this forms the basis of NSAIDs discontinuation) • Animal models suggest a potential benefit • Spargias et al. (Circ. 2009) RCT 208 patients –iloprost (PGI2 analog) found CIN 8% vs. 22%, p=0.005 • No longer term effect investigated • Study powered for 70% reduction in CIN-clinically implausible • Large clinical trials needed before able to recommend

  39. Renal perfusion and diuresis Ascorbic acid, an antioxidant was found to be associated with less CIN in 2-3 gm/day doses before and after the procedure in one study (Spargias et al. Circ. 2004) Calcium channel blockers were found to have no effect on the incidence of CIN

  40. Theophylline Stacul et al. (Am J Cardiol, 2006) found significant benefit of adenosine antagonist administration (theophylline and aminophylline) Kelly et al. Ann Intern Med. 2008

  41. ACE inhibitors • ACEi/ARB play an integral role in cardiac patient care, DM nephropathy prevention, AMI, HTN • Angiotensin II is a potent vasoconstrictor, stimulator of vasopressin and aldosterone • Xiong et al. (Pharmacol Res 2006) demonstrated that irbesartan attenuates CIN renal tubular cell apoptosis by reducing oxidative stress • Gupta et al. (Indian Heart J 1999) showed that captorpil reduced CIN in DM patients by 79% • Dangas et al. (AM J Cardiol 2005) ACEi reduces risk of CIN in CKD patients

  42. ACE inhibitors • Holscher et al. in a 412 pt study found ACEi associated with CIN (Can J Cardiol 2008), Toprak et al. found similar results in 2003 • Cirit et al. evaluated chronic ACEi users and found that ACEi increases the likelihood of CIN, likely due to decrease in glomerular hydrostatic pressure • Rosenstock et al. published the largest RCT to date on ACEi and CIN. 283 patients, three groups (ACEi cont, ACEi discont, ACEi naive). IVF and NAC were used. Found no significant difference.

  43. Available studies for ACEi and CIN Patel K, King C, Jovin IS Cardiovasc Revasc Med 2011, 90-93

  44. McGuire VAMC study • 2201 mostly (98%) male patients, retrospectively analyzed from Janury 2003 until September 2005. • Average follow up 65 months. • Risk factors, interventions collected • We were interested if IVF administration, ACEi, NAC or statin therapy has any benefit on CIN and beyond the traditional definition (at 3 months and for risk of HD) • We included diagnostic cardiac catheterization and PCI/PEI • Included patients with all creatinine levels

  45. McGuire VAMC study

  46. McGuire VAMC study-IVF

  47. McGuire VAMC study -ACEi

  48. McGuire VAMC study - statin • CIN occurred in 3% patients in the statin group and 3.6% in the no statin group at 72 hours after the procedure OR 0.82 (0.43 – 1.55) P=0.54 • At 3 months, CIN was seen in 7.8% patients of the statin group versus 7.9% of the no statin group OR 0.99 (0.64 – 1.51) P=0.95 • The Cox proportional hazard ratio for starting HD in people on statin at the time of catheteriation was 0.88 (0.44-1.77) p=0.72

  49. McGuire VAMC study-Mucomyst • The NAC treated group was significantly older, had significantly more CAD, CHF, DM, and higher baseline creatinine (mean 1.75 vs. 1.20) • CIN occurred in 5.6% patients in the NAC group and in 2.7% in the no NAC group at 72 hours after the procedure OR 2.14 (1.08 – 4.23) • At 3 months, CIN was seen in 13.5% patients of the NAC group versus 6.8% of the no NAC group OR 2.14 (1.36-3.3) p=0.0008 • NAC was administered to a significantly sicker population with a much higher risk of CIN development, but NAC preventitive therapy did not seem to have a protective effect

  50. General limitations in the literature • Most studies without placebo/control group • Different baseline characteristics among studies-different risk for CIN/CIAKI • Different interventions for prevention (different IVFs with or without NAC or other interventions) not consistent among studies • Different CM administration (cardiac cath, +/- PCI, IV contrast) • Studies have limited number of patients

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