CI-AKI

1. Contrast Induced
Acute Kidney Injury

2. Contrast-induced nephropathy (CIN) is generally a reversible
form of acute kidney injury (AKI) that occurs soon after the
administration of radiocontrast media.
Sandler CM. Contrast-agent-induced acute renal dysfunction – is iodixanol the answer? N Engl J Med.
2003;348(6):551–3.

3. Mehran R, Nikolsky E. Contrast-induced nephropathy: definition, epidemiology, and patients at risk.
Kidney Int Suppl. 2006(100):S11–5.
an absolute
increase in serum
creatinine of ≥0.5
mg/dL or a ≥25%
relative increase
in serum
creatinine from
the baseline value
at 48–72 hours
after exposure
to contrast
agent, peaks at
3–5 days
in the absence
of alternative
causes for
acute kidney
injury
Definition:

4. KDIGO Definition
CI-AKI is defined by the Kidney Disease Global Outcomes
(KDIGO) guidelines as an “increase in serum creatinine of 0.3
mg/dL or greater within 48 hours of contrast use or a 50% or
greater increase from baseline serum creatinine within 7 days”
• or an increase in cystatin C >10%
From Kidney disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group.
KDIGO CLINICAL PRACTICAL GUIDELINES FOR ACUTE KIDNEY INJURY.
Kidney Int 2012;Suppl 2:1 -138;

5. Is relative increase in serum creatinine more important than
absolute increase in serum creatinine, does it matter much?

7. 1 2 3 4 Weeks
Serum
Creatinine
In most cases, the
decline in renal
function is mildand
transient
S. Cr. usually returns
to the baseline value
after 1–3 weeks
Some patientshave
a persistent decline
in renal functionand
requireRRT
(in patients with CIN
risk factors)

8. CI -AKI Cholesterol Embolization
INCIDENCE 2% (14.5%) 0.15% (usually underestimated)
At risk CKD, DM2 Abdominal aortic aneurysm,
Diffuse atherosclerosis
Prediction Risk score Episodic HTN, eosinophilia
Signs Usually asymptomatic Signs of peripheral
embolization (livedo reticularis,
abdominal foot pain, purple
toes
Decreased urine output
Course Develops within in 24-48 hrs Develops slowly over weeks to
months.
Returns to baseline in 1-3
weeks
Progress to frank renal failure
(50%)
Renal replacement therapy -
dialysis
Usually not needed (2%) Half of the patient progress to
frank renal failure requiring
dialysis

9. Incidence
of CIN
Risk
Factors
Contrast
Dose
Type of
Radiologic
procedure
Contrast
Type

10. According to the FDA, the incidence of renal failure after
contrast administration, ranged from 0.6% to 2.3%.
However, rates of CIN may be as high as 50%, depending on
the presence of well characterized risk factors, the most
important of which are baseline chronic renal insufficiency
and DM.
Rihal CS, Textor SC, Grill DE, et al. Incidence and prognostic importance of acute renal failure after
percutaneous coronary intervention. Circulation. 2002;105(19):2259–2264.

11. 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%.
• Differential diagnosis: cholesterol embolism : can be difficult
to distinguish: in elderly men, may have cutaneous signs.
Nash et al. Am J Kidney Dis 2002

12. Mortality Risk:
• Rihal et al. 2002, in a 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% Creatinine increase and
one year mortality (Gruberg et al, 2000).

13. How to Assess Renal Function?
Abbreviated Modification of Diet in Renal Disease equations
(MDRD) equation:
eGFR, ml/min/1.73 m2= 186 x (Serum Creatinine [mg/dL]) -1.154 x (Age-
0.203x (0.742 if female) x (1.210 if African American)
(140- age) x Body Weight [kg]*
Creatinine Clearance, ml/min =
* Multiple by 0.8 in female
Cockcroft-Gault equation:
Serum Creatinine mg/dL] x 72

14. Pathophysiology:
• Poorly understood, complex syndrome, little known about underlying
cellular mechanism.
• Available contrast media: 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

15. • Endothelins (if contrast >150 ml), adenosine (prolonged
vasoconstriction, A1 receptors) and angiotensin II released
causing vasoconstriction.
• Nitric oxide 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.

16. • Chronic Kidney Disease (CKD) predisposes to the development
of contrast-induced acute kidney injury (AKI).
• 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.

17. Factors Involved In CIN Pathogenesis

18. 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

19. Risk Factors:

20. To assess the cumulative risk of several variables on renal
function, a simple CIN risk score that could be readily applied was
developed.

21. Predicting the Risk of CIN after PCI
Mehran R, Aymong ED, Nikolsky E, et al. A simple risk score for prediction of contrast-induced nephropathy after
percutaneous coronary intervention: development and initial validation. J Am Coll Cardiol 2004;44:1393-9.
CIN

22. • There is no specific treatment once CI-AKI develops, and
management must be as for any cause of ATN, with the focus on
maintaining fluid and electrolyte balance.
• The best treatment of contrast-induced kidney injury is
prevention.
Prevention

23. Imaging studies not requiring• Consider alternate
contrast medium.
• The use of lower doses of low or iso-osmolal nonionic contrast
agents and avoidance of repetitive studies that are closely spaced
(within 48 to 72 hours).
• Avoidance of volume depletion.

24. Contrast agents:

25. • A decreased incidence of contrast nephropathy appears to be
associated with nonionic agents, which, are either low osmolal
(500 to 850 mosmol/kg) or iso-osmolal (approximately 290mosmol/kg).
Lautin EM, Freeman NJ, Schoenfeld AH, et al. Radiocontrast-associated renal dysfunction: a comparison of lower
osmolality and conventional high-osmolality contrast media. AJR Am J Roentgenol 1991;157:59.

26. IODIXANOL vs. LOCM
• NEPHRIC trial: iodixanol vs iohexol: diabetics, serum creatinine -1.5 -3.5 mg/dl (3%
vs. 26%, p=0.02).
NEJM 2003;348(6):491-9.
• RECOVER trial: iodixanol vs ioxaglate: (7.9% vs. 17%, p=0.021), in patients with
severe CKD (12.5% vs. 53.3%), diabetics (10.4% vs 26.5%).
JACC 2006;48(5):924-30.
• CARE trial: iopamidol: contrary findings: moderate to severe CKD patients, no
difference in CIN (6.7% vs. 4.4% p=0.39)
Circulation 2007;115(25);3189-96.
• VALOR trial: ioversol: (21.8% vs.23.8%).
Am H J 2008;156(4);776-82.
IMAPCT trial, PREDICT trial, ACTIVE trial: no difference in nephrotoxicity.

27. • 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.

28. • Most of the studies indicate that the higher volume of CM is
especially deleterious in the presence of other risk factors, with
lower doses of contrast being safer, but not free of risk.
• Even relatively low doses of contrast (less than 100 ml) can induce
permanent renal failure and the need for dialysis in patients with
chronic kidney disease.
• Intra-arterial administration is associated with higher rate of CIN
and LOCM is more beneficial over HOCM than with intravenous
use.
Vlietstra RE, Nunn CM, Narvarte J, Browne KF. Contrast nephropathy after coronary angioplasty in
chronic renal insufficiency. Am Heart J 1996; 132: 1049–1050.

29. Studies in 1990’s calculated the dose of contrast to be given to
the patients at risk for CIN:
< 5ml/kg / S. Creatinine (Max. 300 ml)
A ratio of <3.7 for the volume of contrast media to creatinine
clearance has also been proposed as a stricter limit.

30. • Concomitant nephrotoxic drugs such as NSAID and nephrotoxic
antibiotics, ACEI and diuretics should be discontinued 48 hours
prior to contrast administration.
• Metformin should be discontinued on the day of the proposed
CM administration and for the subsequent 48 hours.

32. Goals of Hydration
• Maintain of sufficient intravascular volume to increase renal
perfusion.
• Establishment of adequate diuresis prior to contrast media.
• Avoidance of hypotension.
• 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%)

33. • Isotonic saline is superior to one-half isotonic saline since isotonic
saline is a more effective volume expander.
• In a study by Mueller et al, intravenous administration of isotonic
saline was found to be superior, compared with half-isotonic
saline, in reducing the rates of CIN after percutaneous coronary
intervention (0.7% versus 2%, respectively).
Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy:
randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty.
Arch Intern Med. 2002;162(3):329–336.

34. Since alkalinization may protect against free radical injury, the possibility that
sodium bicarbonate may be superior to isotonic saline has been examined
in a number of randomized trials and meta-analyses.
BOSS (Bicarbonate or Saline Study): TCT 2013, no difference in the
incidence of CIN in patients with CKD 3,4,5 undergoing CAG.
• The results were conflicting as some showed a significantly lower rate of
contrast-induced nephropathy with sodium bicarbonate, while others found
equivalent rates.
• 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
• Briguori C, Airoldi F,D'Andrea D, et al. Renal Insufficiency Following Contrast Media Administration Trial
(REMEDIAL): a randomized comparison of 3 preventive strategies. Circulation 2007; 115:1211.
• Vasheghani-Farahani A, Sadigh G, Kassaian SE, et al. Sodium bicarbonate plus isotonic saline versus saline for
prevention of contrast-induced nephropathy in patients undergoing coronary angiography: a randomized
controlled trial. Am J Kidney Dis 2009; 54:610.

35. • IVF = 1 mL/kg/hr (Max 100 ml/hr) 12 hours
pre & 12 hours post contrast
• CHF or left ventricular ejection fraction (LVEF)
<40%?
0.5 ml/kg/hr (Max 50 ml/hr) 12 hrs pre & post
contrast
• Emergent procedure? (suggestedregimen):
Fluid bolus of 3ml/Kg prior to procedure.
Hydration during procedure and 12 hrs after if
possible (dependent on clinical status)

36. • Given that an increasing number of individuals receive contrast as
outpatients, this trial has evaluated the effectiveness of oral hydration in
preventing contrast nephropathy.
• 53 patients were randomly assigned to either unrestricted oral fluids or
to normal saline at 1 mL/kg per hour for 24 hours beginning 12 hours
prior to the scheduled catheterization. AKI was significantly more
common with oral hydration (35 versus 4 %).

37. IVF = 150 meq of sodium bicarbonate in 850 ml ofD5W
3 ml/kg bolus (Max 300 ml) 1 hour prior to procedure and 1
mL/kg/hour (Max 100 ml/hr) during and for 6 hours post-
procedure.
Glycemic control issues (including patients with diabetes)?
Consider mixing sodium bicarbonate in 1 liter of sterile water
instead of D5W

38. • There are great heterogeneity and conflicting results
available clinical trials and meta-analyses examining
in the
the
in the prevention of contrasteffectiveness of acetylcysteine
nephropathy .
• Being a precursor for glutathione synthesis, NAC has the potential
to diminish oxidative stress by directly scavenging superoxide
radicals and increasing intracellular glutathione.
Drager LF,Andrade L, Barros de Toledo JF, Laurindo FR, Machado Cesar LA, Seguro AC. Renal effects of N
acetylcysteine in patients at risk for contrast nephropathy: decrease in oxidant stress-mediated renal tubular
injury. Nephrol Dial Transplant. 2004;19(7):1803–7.
N acetyl Cysteine

40. • This trial studied 83 patients with chronic renal insufficiency who
were undergoing computed tomography.
• Patients were randomly assigned either to receive the antioxidant
acetylcysteine (600 mg orally twice daily) and 0.45 percent saline
intravenously, before and after administration of the contrast
agent, or to receive placebo and saline.
• Conclusion:
Prophylactic oral administration of acetylcysteine, along with
hydration, prevents the reduction in renal function induced by the
contrast.

41. • 2308 patients undergoing angiography received either
acetylcysteine (1200 mg orally twice daily) or placebo on the day
before and after angiogram.
• Patients had at least one of the following risk factors: age >70
years, CKD, diabetes mellitus, heart failure or LV ejection fraction
<45 percent, or shock.
• There was no difference in the development of CI-AKI (12.7
percent in both groups).

42.  Since the agent is potentially beneficial, well tolerated, and relatively inexpensive, 2012
KDIGO guidelines that suggest administration of acetylcysteine to patients at high risk.
AcetylcysteineDosing
Tolerating POintake?
600-1200 mg capsules PO Q12h X 4doses
2 doses pre-contrast and 2 doses post-contrast isoptimal
Emergent Procedure?
1 dose before and 3 doses post cath or procedure is acceptable (Q12h x 4 doses
total)
IV Acetylcysteine?
600-1200 mg IV x 1 over 15 minutes, then 600-1200 mg PO/PT q12h x 4 doses
post-procedure: For a high risk patient undergoing cardiac catheterization or
PE protocol CT scan with no POaccess

43. • Statins may improve endothelial function, reduce arterial
stiffness, and reduce inflammation and oxidative stress.
• There are no sufficient data to support the use of statins solely for
the prevention of contrast nephropathy.
Sugiyama M, Ohashi M, Takase H, et al. Effects of atorvastatin on inflammation and oxidative stress.
Heart Vessels 2005; 20:133.
Statins

44. • 2998 patients with type 2 diabetes and CKD were assigned to receive
rosuvastatin or to a control group prior to a diagnostic angiogram with
or without percutaneous intervention.
• Patients assigned to rosuvastatin received 10 mg daily two days prior
and three days after the scheduled procedure.
• Contrast-induced was less common among patients assigned to
rosuvastatin compared with control (2.3 versus 3.9 percent,
respectively).

45. • A prospective, single-center study of 304 patients with baseline
estimated creatinine clearance <60 ml/min were randomized to receive
atorvastatin 80 mg/day or placebo for 48 hours before and 48 hours
after contrast medium administration.
• All patients received intravenous saline hydration and oral N-
acetylcysteine 1,200 mg 2 times/day.
• CIN occurred in 31 patients, 16 (11%) in the placebo group and 15 (10%)
in the atorvastatin group (no benefit of atorvastatin compared with
placebo).

46. • PRATO-ACS Trial: Benefit seen.
• 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 the time
of administration
• Dose of beneficial statin uncertain

47. • Low-dose dopamine failed to show a protective effect on renal function
in patients undergoing contrast media exposure, and was even
associated with a deleterious effect on the severity of renal failure and
its duration.
Gare M, Haviv YS, Ben-Yehuda A, et al. The renal effect of low-dose dopamine in high-risk patient
undergoing coronary angiography. J Am Coll Cardiol. 1999;34(6):1682–1688.
Dopamine

48. • Fenoldopam is a specific dopamine-1 receptor agonist that augments
renal plasma flow while decreasing systemic vascular resistance.
• A prospective randomized trial (CONTRAST) assessed the effectiveness
of fenoldopam in 315 patients undergoing a cardiovascular procedure
who had CKD with an estimated creatinine clearance <60 mL/min.
• Unfortunately it also fails to reduce CIN incidence in CKD patients.

49. Vasoactivedrugs
• In a retrospective series of 285 patients, Weisz et al. reported a 71%
decreased in CIN incidence with local fenoldopam therapy (0.05–0.8
μg/kg/min).
Weisz G, Filby SJ, Cohen MG, Allie DE, Weinstock BS, Kyriazis D, et al. Safety and performance of
targeted renal therapy: the Be- RITe! Registry. J Endovasc Ther. 2009;16(1):1–12.

50. Theophylline
• The clinical benefit of the competitive adenosine antagonist
theophylline is debated.
• In a randomized study by Huber et al, prophylactic intravenous
administration of theophylline 200 mg reduced the incidence of CIN in
100 patients at risk, as compared with placebo (4% versus 16%).
• However, in other randomized studies, administration of theophylline
did not provide any benefit in reduction of CIN rates compared with
placebo.
Huber W, Ilgmann K, Page M, et al. Effect of theophylline on contrast material-nephropathy in patients with
chronic renal insufficiency: controlled, randomized, double-blinded study. Radiology. 2002; 223(3):772–779.
• Shammas NW, Kapalis MJ, Harris M, McKinney D, Coyne EP. Aminophylline does not protect against radiocontrast
nephropathy in patients undergoing percutaneous angiographic procedures. J Invasive Cardiol. 2001;13(11):738–
740.

51. Prostaglandins E1
• A 20 ng/kg/min PGE1 infusion has a significant protective
effect on post-PCI SCr elevation.
• But higher infusion rates are not associated with increased
benefits, probably due to the associated decrease in
systemic blood pressure.
Koch JA, Plum J, Grabensee B, Modder U. Prostaglandin E1: a new
agent for the prevention of renal dysfunction in high risk patients
caused by radiocontrast media? PGE1 Study Group. Nephrol Dial
Transplant. 2000;15(1):43–9.

52. Calcium channel Blockers
• In a small, randomized, placebo controlled study of 35
patients, eGFR was preserved in patients treated with
nitrendipine but decreased in patients that received placebo.
Neumayer HH, Junge W, Kufner A, Wenning A. Prevention of radiocontrast-media-induced
nephrotoxicity by the calcium channel blocker nitrendipine: a prospective randomised
clinical trial.Nephrol Dial Transplant. 1989;4(12):1030–1036.
• By contrast, in three other studies, the change in serum
creatinine level did not differ significantly with calcium
antagonists.
Carraro M, Mancini W, Artero M, et al. Dose effect of nitrendipine on urinary enzymes and
microproteins following non-ionic radiocontrast administration. Nephrol Dial Transplant.
1996;11(3):444–448.

53. Atrial Natriuretic Peptide:
• Morikawa et al. (JACC 2009) single center RCT ANP+IVF or IVF alone
• ANP at 0.042 mcg/kg/min 4-6 hours prior and 48 hours past
• eGFR at 24, 48 hours, 1 week and 1 month
• Slight benefit of ANP in Creatinine, no benefit in HD/ Hospital rate
admission
• Prior studies were negative, but this one had lower ANP dose for longer
time
• No conclusive evidence yet, would need larger trials.

54. Methods to guide fluid repletion
Left ventricular end-
diastolic pressure
RenalGuard System
Brar SS, Aharonian V,Mansukhani P, et al. Haemodynamic-guided fluid administration for the prevention of contrast-
induced acute kidney injury: the POSEIDON randomised controlled trial. Lancet 2014; 383:1814.
Briguori C, Visconti G, Focaccio A, et al. Renal Insufficiency After Contrast Media Administration Trial II (REMEDIAL II):
RenalGuard System in high-risk patients for contrast-induced acute kidney injury. Circulation 2011; 124:1260.

55. Left ventricular (LV) end-diastolic pressure

56. • A randomized trial tested the benefit of a fluid replacement protocol
guided by LV end-diastolic pressure among patients with CKD and other
risk factors for CIN.
• In this trial, 350 patients were assigned to LV end-diastolic pressure-
guided fluid management or to a control group.
• All patients received intravenous isotonic saline 3 mL/kg for one hour
prior to cardiac catheterization. LV end-diastolic pressure was
determined in all patients prior to administration of contrast.

57. • Both groups received intravenous fluid throughout and for four hours
following the procedure.
IV infusion
rate
LVend-diastolic
pressure
<13 mmHg
5 mL/kg/hour
13 - 18 mmHg
3 mL/Kg/hour
>18 mmHg
1.5 mL/Kg/hour
Control 1.5 mL/kg/hour
Contrast-induced
AKI occurred less
frequently in the LV
end-diastolic
pressure group,
compared with
control (6.7 versus
16.3, respectively).

58. RenalGuard system

59. Forced diuresis (RenalGuard System):
Treatment protocol for the RenalGuard System. Source: Reproduced with
permission from PLC Medical Systems.

60. • Contrast-induced acute kidney injury occurred in 16 of 146 patients in
the RenalGuard group (11%) and in 30 of 146 patients in the control
group (20.5%).
• Conclusion:
RenalGuard therapy, including hydration with normal saline plus high
doses of NAC in combination with a limited (0.25 mg/kg) dose of
furosemide, seems to be an effective renoprotective strategy for
patients at high risk for CI-AKI.

62. The CI-AKICOR System
Comprises an 11Fr coronary sinus aspiration
catheter that is inserted through the jugular
vein. On activation,it exerts a vacuum effect
and removes contrast from the coronary
sinus.

63. Hemodialysis
• Iodinated contrast agents are readily dialyzable.
• The plasma clearance of most modern contrast media is 50–70 mL/ min,
with more than 80% removed from the plasma within 4–5 hours of
hemodialysis.
• However, Reduction of CIN with dialysis is also not biologically plausible
since the CM would reach the kidneys within one or two cardiac cycle.
• Subsequent removal of CM is unlikely to stop the cascade of renal
injury, which would have already begun.
Dawson P. Contrast agents in patients on dialysis. Semin Dial. 2002;15(4):232–236.

64. Hemofiltration
• In patients with chronic renal failure who are undergoing
percutaneous coronary interventions, periprocedural
hemofiltration given in an ICU setting appears to be effective in
preventing the deterioration of renal function due to CIN and is
associated with improved in-hospital and long-term outcomes.
Marenzi G, Marana I, Lauri G, et al. The prevention of radiocontrast-agent-induced nephropathy by
hemofiltration. N Engl J Med 2003; 349:1333.

65. • A 2012 meta-analysis that included eight studies of hemodialysis
and three studies of hemofiltration/hemodiafiltration showed no
benefit of RRT.
• Routine hemofiltration or hemodialysis for the prevention of
contrast nephropathy in patients with CKD is not recommended.
Cruz DN, Goh CY,Marenzi G, et al. Renal replacement therapies for prevention of radiocontrast-
induced nephropathy: a systematic review. Am J Med 2012; 125:66.

66. Novel Approaches:
Large studies of Oral/ Intravenous antioxidants (Deferiprone).
Intrarenal infusions of renal vasodilators using flow directed
catheters.
Systemic Cooling.
Novel, less toxic forms of radio - opaque contrast agents.

67. Take Home Message !!