- Contrast-induced acute kidney injury (CI-AKI) is a common cause of hospital-acquired acute kidney injury and is caused by the vasoconstrictive effects of iodinated contrast media during imaging procedures. - The risk of CI-AKI increases significantly with reduced kidney function and other risk factors such as diabetes, dehydration, and older age. Proper hydration helps prevent CI-AKI by increasing renal blood flow and diluting the contrast in the kidneys. - While IV hydration with crystalloids remains the most effective preventive measure, the optimal hydration protocol has not been firmly established.

1. Contrast-induced
Acute Kidney Injury
DM Seminar
Dr. Vishal Golay
16/11/11

2. • Iodinated contrast medium was first used in 1954.
• Association of contrast use with renal impairment was
first made with use of iodopyracet, a di-iodinated
pyridine derivative ≥ 50yrs ago
45
Recognition of high risk groups.
40
35
30
25
20 Prevention
15 controversy
10
5
0
1960 1970 1980 1990 2000

3. • It is one of the common causes of AKI
hospitalized patients.
• CI-AKI was reported to be the third most
common cause of AKI in hospitalized patients.
Nash et al. AJKD 2002;39:930-6.
• Reported incidence varies from 1.7-2% of
patients without predisposing factors and up to
10-45% of patients with predisposing factors.

4. All agents are chemical modifications of a 2,4,6-tri-iodinated benzene ring.

5. Contrast agents
Class Agents Osmolality Osmolality
(msom) (compared to
plasma)
High- Ionic Iothalamate 1400-2000 5-8
osmolar monomers (conray)
Diatrizoate
(hypaque)
Metrizoate
Low- Non-ionic Iohexol 600-800 2-3
osmolar monomers (omnipaque)
Ioversol (optiray)
Iopamidol
Iopromide
Ionic dimer Ioglaxate
Iso-osmolar Nonionic Iodixanol(visipaque) 300 1
dimer Iotrolan

6. CIN consensus working panel(2006)
• Consensus statement 6: In patients at increased risk for CIN
undergoing intra-arterial administration of contrast, ionic high-
osmolality agents pose a greater risk for CIN than low-
osmolality agents. Current evidence suggests that for intra-
arterial administration in high-risk patients with chronic kidney
disease, particularly those with diabetes mellitus, nonionic,
iso-osmolar contrast is associated with the lowest risk of CIN.
• Consensus statement 7: Higher contrast volumes (>100 mL) are
associated with higher rates of CIN in patients at risk. However,
even small (30 mL) volumes of iodinated contrast in very high-
risk patients can cause CIN and acute renal failure requiring
dialysis, suggesting the absence of a threshold effect.
• Consensus statement 8: Intra-arterial administration of
iodinated contrast medium appears to pose a greater risk for
CIN above that with intravenous administration.

7. CARE Study
• It was a multicenter, randomized, double-blind
comparison of iopamidol and iodixanol in patients (414
pts) with chronic kidney disease (eGFR, 20 to 59
mL/min) who underwent cardiac angiography or PCI.
• There was no statistical difference in the development
Radiology 250(1); January 2009
of CI-AKI after IA inj of either of the agents even in
Iodixanol is not associated with a significantly reduced risk
those with and without diabetes.
of CIN compared with the LOCM pooled together.
• Thus, either agent can be safely used for coronary
interventions in patients with renal insufficiency
Circulation. 2007;115:3189-3196

8. Left ventricular &-----: 30-45 mL
aortic angiography
PCI-----------------------:150-200 mL
CECT scan--------------:uses 100-150 mL
IVU-----------------------:100-mL bolus of a 50%–60%
(weight-to-volume ratio) contrast
material.
FFA uses Na fluorescein and not assoc with CIN

9. Definition
• In 2008, contrast-induced acute kidney injury (CIAKI)
was proposed as the consensus name for what was
formerly termed ‘contrast-induced nephropathy’
Arch. Intern. Med. 168, 1325–1332 (2008).
Defined by a fixed (0.5 mg/dl [44 μmol/L]) or
proportionate (25 %) rise in serum creatinine
levels assessed 48 hours after exposure to the
contrast medium, in the absence of any other
apparent cause.

10. Risk factors
Patient related factors:
• Renal insufficiency.
• Diabetic Nephropathy. • Concomitant exposure to
• Advanced age (>75 yrs). nephrotoxins
• Effective volume • Myeloma
depletion- • Male gender.
– Dehydration. • Hypertension
– CHF. • Transplanted kidney
– CLD • Hyperuricemia
– Nephrotic syndrome
• Proteinuria
– Hypotension
• Anemia

11. Risk factors contd…..
Procedure related factors:
• Type of radiocontrast medium (HOCM>LOCM/IOCM).
• Dose of contrast used.
• Repeated exposure to radiocontrast material within 72
hours.
• Mode of administration (IA>IV)
• Primary coronary intervention for acute MI

12. 120
Risk factors contd…..
100
•80 Many risk factors are covariates rather than
independent variables. This may account for reports
60 that fail to determine causality of independent
variables.
40
• Incidence increases proportional to the number of
20
cosexisting risk factors.
0
0 1 2 3 4
number of risk factors
Arch Intern Med 1990;150

13. Renal insufficiency & risk of CI-AKI
• The risk of CIAKI increases marked when CCl<60ml/min
& rises further when other risk factors are present.
• Reduced GRF makes the functioning nephrons secrete
greater load of contrast.
• Lack of functional reserve to buffer acute losses in
glomerular filtration.
• Studies show that risk dramatically increases at lower
GFR.

14. Evaluation of risk
• Proper history and physical examination is imperative.
• Various risk-prediction models have been developed
for pts undergoing PCI.
• Serum creatinine at baseline should be checked if the
contrast is being given IA or any risk factors are
present. GFR should be calculated.
• Always consider alternate imaging techniques in those
with risk factors.

15. N Engl J Med 2006;354:379-86.

16. Course and Prognosis
Creat rise Creat peak Return to
baseline
In a study on 200 patients undergoing PCI
for acute MI, patients who developed CIN had a
Non-oliguric 48hours longer hospital stay (13 ±7 days as compared
3-5 days 10-14days
CIAKI with 8 ±3 days in subjects without CIN; p<0.001)
and a more complicated clinical course, in
Oliguric CIAKI 48 hours addition to a significantly increased risk of
5-10 days 14-21 days
death.
J Am Coll Cardiol 2004;44:1780 –1785
• 1% may need dialysis & in those with severe involvement, 30% may
have residual renal impairment..
• At 1 year after PCI, the mortality rate in patients undergoing dialysis
had increased to 45.2%, compared with 35.4% in patients with CIN
not requiring dialysis and 19.4% in patients who did not develop CIN.

17. Pathogenesis

18. Oxidative
stress
Direct
tubular
toxicity
Contrast Induced AKI

19. Vasoconstriction
• CIAKI is primarily an ischemic form of AKI caused by the
vasoconstrictive properties of contrast media.
• Animal studies show a biphasic response after contrast
injection. There is an initial renal vasodilation followed
by intense and prolonged (3 hrs) vasoconstriction.
• There is a selective decrease in the medullary blood
flow and oxygen saturation due to an imbalance
between vasodilators and vasoconstrictors

20. • The principal vasoconstrictors are Adenosine and
Endothelin.
• Contrast media seem to reduce renal blood flow
directly through afferent arteriole vasoconstriction via
activation of adenosine receptor A1.
• In concert, contrast agents also disrupt the vasodilatory
systems like NO and prostaglandins bringing about an
intense vasocontriction and reduced medullary bloos
supply

22. Oxidative stress
• The intense vasoconstriction and loss of autoregulatory
capacity can contribute to additional renal injury
through the release of reactive oxygen species (eg,
superoxide [OH].).
• Damage is due to overwhelming of the anti-oxidant
factors by the excess generation of ROS.
• Underlying diseases like CKD and Diabetes already have
high ROS and thus predisposes for CIN.
• Benefit of anti-oxidants gives an indirect clue.

23. Direct tubular toxicity
• Marked osmotic diuresis is observed following contrast
administration.
• “osmotic nephrosis”
• The most common histopathologic features of this
disorder include intense focal or diffuse vacuolization
of the proximal tubules or overt tubular necrosis.

25. Prevention of CI-AKI

26. • Only 40% of patients with GFR <60ml/min receive any
form of preventive measures.
• Even when they do so, the strategy is not a
standardized one.

27. Hydration
• The benefit of hydration in prevention was
detected by retrospective analysis, and trials on
benefit of hydration is limited by absence of
controls.
• However, it remains the most efficient method of
prevention of CI-AKI.
• IV crystslloids are given @1-
1.5ml/kg/hr, beginning 12 hrs before the
procedure and continuing up to 6-24 hrs after it.

28. Hydration contd….
The mechanisms by which IV hydration decreases the risk
of CI-AKI are:
• IV half-normal (0.5 N) saline may cause an increase in
free water excretion, leading to dilution of the contrast
agents within the tubule lumen.
• 0.9% saline was found better probably due to increased
delivery of sodium to the distal nephron, leading to
reduced activation of the RAS via the macula densa.
• Intravenous volume expansion would also minimize
reductions in the renal production of nitric oxide.

29. Hydration contd….
• Mueller et al compared hydration with 0.45% and 0.9%
NaCl in 1620 patients who were undergoing cardiac
catheterization. The incidence of CIN was 2% and 0.7%
respectively (p=0.04). The benefit was more in those
with diabetes.
Arch. Intern. Med. 162, 329–336 (2002).
• Two small studies suggest that sustained fluid
administration within 12 h before and within 12 h after
administration of contrast medium is superior to bolus
administration at the time of contrast administration
Clin. Nephrol. 62, 1–7 (2004).
J. Invasive Cardiol. 15, 699–702 (2003).

30. Hydration contd….
• In an emergency situation full preprocedure volume
expansion is not possible, and there is a lack of published
evidence to guide clinicians about appropriate alternatives.
• The CIN Consensus Working Panel agreed that in emergency
situations, where the potential benefit from an urgent
investigation outweighs the risks of waiting, the procedure
can be undertaken without knowledge of renal function,
which precludes risk stratification according to renal
function.
• Hence, clinical judgment is needed.
• Appropriate postprocedure intravenous fluids should be
given.

31. Sodium bicarbonate
• The beneficial role of sodium bicarbonate was first
studied by Merten et al. (RCT of 119 patients).
Significant reduction in CIN with NaHCO3 as compared
to NaCl infusion.
JAMA 291, 2328–2334 (2004)
.
• NaHCO3 is given at a dose of 3ml/kg/hr infusion for 1
hr before procedure of a 154mEq/L NaHCO3 solution
which is continued post procedure @ 1mL/kg/hr for 6
hours.

32. Sodium bicarbonate contd…
• The role of bicarbonate is unclear and controversial. It
might be related to an increase in tubular fluid pH level
and prevent the formation of free radicals.
• But bicarbonate is a pro-oxidant specially in the
presence of ROS.
• In vitro studies also showed that although NAC and
ascorbic acid prevented contrast induced apoptosis of
tubular cells, bicarbonate failed to do so.

33. Trials those who included patients with CKD2-4 as well as
normal renal function.
1. This metanalysis highlights that the perceived benefit of
sodium bicarbonate is largely driven by
small, underpowered RCTs with extreme treatment effects
and wide CIs.
2. Among the large randomized trials there was no evidence
of benefit for hydration with NaHCO3 compared with NaCl
for the prevention of CI-AKI.
Clin J Am Soc Nephrol 4: 1584–1592, 2009

34. 1. Although the summary of the published data favours
bicarbonate but this is due the effect of the smaller, poorer
quality trials .
2. In summary this metanalaysis concluded that the benefit of
bicarb may be over-estimated and the routine clinical use
recommendation maybe still premature

36. This meta-analysis demonstrated a higher incidence of CI-AKI
than recently reported, with important variation among different
Cohorts
There was a protective effect of sodium bicarbonate on the
risk of CI-AKI, especially in patients who underwent coronary
procedures and those with CKD, without effect on need for RRT or
mortality.
Due to the borderline statistical significance, the relative low
quality of the individual studies, heterogeneity and publication bias,
only a limited recommendation can be made in favour of the use of
sodium bicarbonate.

37. N-Acetylcysteine
• Due to the role of ROS in the pathogenesis of CI-AKI it was
postulated that NAC, an antioxidant may be helpful in
The ambiguity the development of CI-AKI.have been due to
preventing of these initial results could
many factors. The main reasons could have been:
• NAC induces glutathione
1. The dose of NAC was low. synthesis. It also plays a role in
counteracting vasoconstriction by ↑NO
2. The ROS generation lasts much longer than anticipated.
3. It is the peak levels of NAC during the procedure that is more
• important. was reported by Tepel et al in 2000 in a trial
First benefit
published in NEJM. (NAC+hydration was compared with
hydration with 0.45% NaCl alone).
• Some other trial published after that showed ambiguous
results.

38. This MA failed to provide conclusive proof of benefit in favor of NAC

39. N Engl J Med 2006;354:2773-82.
354 consecutive patients undergoing primary angioplasty
were randomized to one of three groups:
1. 116 patients were assigned to a standard dose of NAC
(a 600-mg intravenous bolus before primary
angioplasty and 600 mg orally twice daily for the 48
hours after angioplasty),
2. 119 patients to a double dose of NAC(a 1200-mg
intravenous bolus and 1200 mg orally twice daily for
the 48 hours after intervention),
3. 119 patients to placebo.

40. • The serum creatinine concentration increased 25 % or
more from baseline after primary angioplasty in 39 of
the control patients (33%), 17 of the patients receiving
standard-dose N-acetylcysteine (15 %), and 10 patients
receiving highdose N-acetylcysteine (8%, P<0.001).
• NAC has a dose dependent reduction in the risk of
developing CI-AKI with a p<0.001 for this dose-trend.
• Similar findings were also confirmed by 2 earlier trials
the RAPPID study. J Am Coll Cardiol 2003;41:2114-8.
Eur Heart J 2004;25: 206-11.

41. Current status of NAC
ACT Trial (Circulation. 2011;124:1250-1259)
• RCT on 2308 patients undergoing an intravascular angiographic
procedure with at least 1 risk factor for CIAKI randomized to NAC
1200 mg or placebo.
• The incidence of CIAKI (primary end point) was 12.7% in the NAC
group and 12.7% in the control group (relative risk, 1.00; 95% CI
0.81 to 1.25; P=0.97).
• A combined end point of mortality or need for dialysis at 30 days
was also similar in both groups.
• Consistent effects were observed in all subgroups
analyzed, including those with renal impairment.
Conclusions—NAC does not reduce the risk of CIAKI or other
clinically relevant outcomes in at-risk patients undergoing
coronary and peripheral vascular angiography.

42. Adenosine receptor antagonists
• Adenosine induced vasoconstriction has been
shown to be an important pathogenetic
mechanism in the development of CIAKI.
• When given before contrast media, oral or IV
administered theophylline, a nonselective
adenosine-receptor antagonist, have been shown
to reduce the incidence of CIAKI in many studies.
• Trials have used theophylline in doses of 5 mg/kg
iv, 2.88 mg/kg orally, and 165 mg iv.

43. There was a trend towards reduction in CIAKI use with
theophylline use, and this reduction is comparable with that of
NAC.
The main issue of theophylline use in patients with renal
insufficiency is its safety profile
Role of highly selective A1 receptor antagonists should be
evaluated

44. Other agents

45. Role of extracorporeal therapies
HEMODIALYSIS:
• Contrast medium is dialyzable and there were initial reports
that HD was beneficial in preventing CIAKI.
• Later studies showed that in patients not previously on RRT,
HD had no preventive role even if given within 1 hr or
periprocedural and one study even reports a detrimental
effect.
• However, CIN Consensus working Panel agreed that in
patients with severe renal impairment (eGFr <20 ml/min)
who require contrast-medium administration, hemodialysis
should be undertaken if CIAKI develops.

46. Role of extracorporeal therapies contd….
HEMOFILTRATION:
• Single study on patients with Cr>2mg/dl or GFR <50
ml/min with continuous HF starting 6 hrs before till 24
hrs after the procedure showed HF to be protective.
• However, the fact that HF is not an effective contrast
media removing modality, interruption of HF during
the procedure, good intensive care management of pts
on HF and concomitant medications makes this study
difficult to interpret and HF remains an investigative
tool. Requiring further studies
N. Engl. J. Med. 349, 1333–1340 (2003).

47. REMEDIAL trials 1&2
• REMEDIAL I trial, demonstrated that the combined
strategy of volume supplementation with NaHCO3 &
NAC was superior to the administration of NS & NAC
alone or a combination of NS, ascorbic acid, and NAC in
preventing CI-AKI in patients at low to medium risk.
Circulation. 2007;115:1211–1217.
• Investigators of REMEDIAL II trial used furosemide and
justified its use by results of the PRINCE trial and
theoretical principles.
Circulation. 2011;124:1260-1269

48. REMEDIAL trial II contd…
• It was a multicentric RCT, included pts with
GFR<30 mL/min/1.73 m2 and/or a risk score 11.
• They were randomly assigned to NaHCO3 &
NAC(control group) or hydration with saline and
NAC controlled by the RenalGuard System and
furosemide (RenalGuard group).
• Conclusion—RenalGuard therapy is superior to
sodium bicarbonate and N-acetylcysteine in
preventing AKI in high-risk patients.

49. Renal Guard system
Priming hydration of 250 ml
was given followed by furosemide (0.25
mg/kg) iv to achieve an optimal urine
flow of 300 mL/h.
As soon as the urine flow
reached the target value, the patient
wasmoved into the catheterization
laboratory, and the procedure was
started (procedural phase).
Controlled hydration by the
RenalGuard system continued during
the procedure and for 4 hours after the
procedure (postprocedural phase).
Urine flow was monitored and
maintained at the target value
throughout the procedure and during
the next 4 hours

50. Summary of the preventive
strategies
Hydration remains the most imp strategy.
Needs standardization of dosage
Role of NAC & NaHCO3
Promising agents:
unclear.
Theophylline, statins, CIAKI Safety and low cost , can be
ascorbic acid, PGs
tried
Additional studies
are needed to clear
the confusion

51. Take home message
• CI-AKI is one of the most common cause of Aki in
hospitalized patients.
• It is a preventable condition if the risk factors are
vigilantly detected.
• The pathogenesis and preventive measures remain
unclear and controversial.
• Of all the modalities of prevention, good hydration
remains the only proven methodology.

52. THANK YOU