A ppt about contrast nephropathy: basics, risk factors, comparison of preventive strategies. critical review of POSEIDON trial and brief about PRESERVE trial.

1. Presenter : Manish Kumar Singla
Clinical Nephrology and transplant fellow
University of Toronto
Moderator : Dr Ron Wald
June 17th 2014

2. 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.

3. Definition:
New onset acute kidney injury (absolute Cr rise 0.5
mg- 1 mg/dl or relative, 25%-50% from baseline) after
contrast administration and in the absence of other
etiology
Time course of CI-AKI:
Occurs after 24-48 hrs of contrast
Cr peaks in 3-5days and normalizes in 7-10 days(70%)
In 30%, 3 weeks to return baseline or progress to CKD
Predominantly non-oliguric AKI and with mild
proteinuria

4. Patient-related
Renal insufficiency
Diabetes mellitus*
Intravascular volume depletion
Reduced cardiac output
Concomitant nephrotoxins
Procedure-related
↑ volume of radiocontrast
Multiple procedures w/i 72 hours
Intra-arterial administration
Type of radiocontrast
}
* Diabetes alone not strong risk factor
additive risk

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

6. 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%
FFA uses Na fluorescein and not assoc with CIN

7. 0
20
40
60
80
100
120
0 1 2 3 4
number of risk factors
Arch Intern Med 1990;150

8. How contrast agents cause AKI ?

9. Contrast Induced AKI
Direct
tubular
toxicity
Oxidative
stress

11. A temporary increase in renal transport work
in the thick ascending limb of Henle's loop
( in oxygen consumption)
+
Constriction of medullary capillaries ( in medullary oxygen delivery)
LEAD TO
MEDULLARY ANGINA
Solomon, et al. Kidney Int 1998; 230-242

12. Radiocontrast Administration
CIN
Medullary Hypoxia
Generation
of ROS
Intrarenal
Vasoconstriction
Direct
Cytotoxicity
Rheologic
Effects
Osmotic
Load

13. Universally iatrogenic
Risk factors well characterised
Time of insult largely predictable
Make it amenable to prevention

15. CCB
Loop diuretics*
Mannitol*
Dopamine*
Fenoldopam*
ANP
Hemodialysis*
NAC
Theophylline
Aminophylline
Ascorbic acid
Statins
Hemofiltration
• IVF
Ineffective EffectiveUnclear benefit
* Possibly harmful

16. 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 of procedure and one study even reports a
detrimental effect.

17. Tepel M, et al. N Engl J Med 2000; 343:180-184
0%
5%
10%
15%
20%
25%
%CIN(Scr↑0.5mg/dL@48h)
Control
2%
21%
P=0.01
NAC

18. Publication of this study was followed by a
proliferation of clinical trials evaluating NAC

20. most NAC trials enrolled small numbers of
patients on the basis of large postulated
effect sizes, used small changes in kidney
function as the primary endpoint, and did
not systematically track longer-term
sequelae of CI-AKI.
The inconclusive and contradictory results of
these trials also led to multiple meta-
analyses with conflicting conclusions

21. Meta-analysis

23. Citing these results, 2011 guidelines issued
by the American College of
Cardiology/American Heart
Association/Society for Cardiovascular
Angiography and Interventions state that NAC
is not useful for the prevention of CI-AKI and
recommend against its administration

24. Protective effect unclear
Many studies to date have methodological
flaws
Cheap and benign (in oral form)
Should not be used in lieu of other measures

25. 1994 → present
Provide clinical basis for:
Protective effect of IVF
Deleterious effect of furosemide
Superiority of isotonic IVF
Superiority of IVF to pt-directed oral fluids
Potential benefit of oral NaCl

26. Rate of CIN: 11% 28% 40%
Solomon R, Werner C, Mann D, D’Elia J, Silva P. N Engl J Med. 1994;331:1416-1420.

27. Mueller C, et al. Arch Int Med. 2002; 162:329-336
P=0.04
P=0.35
P=0.93

28. 13.6%
1.7%
0%
2%
4%
6%
8%
10%
12%
14%
NaCl (n=59) NaHCO3
(n=60)
rate of CIN
(8/59)
(1/60)
Merten et al. JAMA 2004;291:2328-2334
P = 0.02

29. Presumed effect size -67%, allowed the study
with small sample size of 260. (33% would
have needed 1300
Switch of one patient would have resulted in
statistically negative study

30. 1. Although the summary of the published data favours
bicarbonate but this is due the effect of the smaller,
poorer quality trials .

31. Clin J Am Soc Nephrol 4: 1584–1592, 20
Trials those who included patients with CKD2-4 as
well as normal renal function.

32. Power curve: the relationship between trial size and power.
Hiremath S , and Brar S S Nephrol. Dial. Transplant.
2010;ndt.gfq279
© The Author 2010. Published by Oxford University Press on behalf of ERA-EDTA. All rights
reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

33. 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.
------CLINICAL EQUIPOISE--------
Clin J Am Soc Nephrol 4: 1584–1592, 20
Trials those who included patients with CKD2-4 as
well as normal renal function.

34. NAC – of unclear benefit
Can use 1200 mg po bid x 2 days
IV fluids beneficial – isotonic >> hypotonic
? Superiority of NaHCO3
Abbreviated regimen OK – 1 hr pre and 4-6 hr
post

35. Dal lake, Kashmir, India

37. Volume?
Duration ?
Very little is known about the optimal rate and duration of
fluid administration around the time of contrast exposure.
So far, no trial has directly compared volume expansion
with isotonic saline at different rates or durations in at risk
populations
Not unexpectedly, these uncertainties might explain, in
part, the non-uniform adoption of volume expansion
strategies.
POSEIDON Trial

38. Poseidon is one of the
twelve Olympian deities of
the pantheon in Greek
mythology.
His main domain is the ocean,
and he is called the "God of the
Sea".
Additionally, he is referred to
as "Earth-Shaker“ due to his
role in causing earthquakes,
and has been called the "tamer
of horses

40. Aimed to investigative different rates of fluid
administration guided by the left ventricular
end-diastolic pressure

41. Between Oct 10, 2010, and July 17, 2012,
All consecutive patients referred to the
cardiac catheterization laboratory at the
Kaiser Permanente Medical Center in Los
Angeles, CA, USA
Funded by Kaiser Permanente Southern
California regional research committee grant

42. eGFR of 60 mL/min or lower
age 18 years or older and
at least one of the following:
diabetes mellitus
history of congestive heart failure
hypertension
age older than 75 years

43. inability to obtain consent from participants
emergency cardiac catheterisation
Renal replacement therapy
exposure to radiographic contrast media within the
previous 2 days
allergy to radiographic contrast media
acute decompensated heart failure
severe valvular heart disease
mechanical aortic prosthesis
left ventricular thrombus
history of kidney or heart transplantation
change in estimated GFR of 7.5% or more per day or a
cumulative change of 15% or more during the
preceding 2 or more days

44. Eligible patients randomized in a 1:1 ratio to
either left ventricular end-diastolic pressure-
guided therapy or a standard fluid
administration protocol
Randomization was stratified by diabetes
mellitus status and N-acetylcysteine use.
This study was partly blinded

46. Creatinine was measured at baseline and
twice afterward between day 1 and 4.
Commercially available 0.9% sodium chloride
used in all patients
A bolus infusion at 3 mL/kg for 1 h was given
to all patients before the procedure

47. Before the administration of contrast media, LVEDP was
measured by placing an angled 5 or 6-French pigtail
catheter in the mid-cavity of the left ventricle.
Fluid rate was adjusted according to the LVEDP as
follows:
5 mL/kg/h for LVEDP lower than 13 mm Hg,
3 mL/kg/h for LVEDP of 13–18 mm Hg, and
1.5 mL/kg/h for LVEDP higher than 18 mm Hg.
The control group was hydrated at 1.5 mL/kg per h.
Infusion was continued for the duration of the
procedure, and for 4 h post-procedure in both groups

48. Primary outcome
Primary endpoint
was increase in the
serum creatinine of
greater than 25% or
0.5 mg/dL from
baseline
Secondary endpoints
components of the
primary endpoint
occurrence of major
adverse events at 30
days and 6 months
:-
composite of all-
cause mortality
myocardial infarction
or renal replacement
therapy

49. Analyses were done with Stata version 12.0
and R version 2.15.3.
All tests were two-tailed, with differences
reported as significant if the p value was less
than 0.05

52. total mean (SD) volume of NS administered
was 1727 ml in LVEDP group vs 812 ml in
control group

53. Overall incidence of CI AKI was 11.4% - it was 6.7 %
in LVEDP group vs 16.3% in control group (p = 0.005)
Relative risk was 0.41 (95% CI 0.22–0.79)
NNT 11

55. Patients who received larger volumes of normal
saline had a lower rate of contrast-induced
acute kidney injury than did those given smaller
volumes
Among patients with LVEDP > 18, incidence of CI
AKI was 5.3% (8/152) in the treatment group
versus 14.4% (21/146) in the control group
(relative risk 0.37, 95% CI 0.17–0.80; p=0.008)
Moreover, the odds of contrast-induced acute
kidney injury decreased by 9% for every
additional 100 mL of normal saline administered
(odds ratio 0.91 p = 0.01)

58. First randomised trial to compare different
rates of volume expansion with normal saline
for the prevention of CI AKI
Clinical assessment of a patient’s
intravascular volume status without
hemodynamic data , and thus their ability to
tolerate high rates of fluid administration, is
difficult and imprecise
LVEDP guided fluid administration protocol
provides a framework for targeted
intravascular volume expansion.

59. Through linkage of the rate of fluid
administration to the LVEDP, the treatment
group was able to receive roughly twice the
volume with a similar rate of fluid
termination than the control group
This resulted in a significant 68% relative
reduction (a 9.5% absolute reduction) in the
primary endpoint of CI AKI and a significant
59% relative reduction (a 6.4% absolute
reduction) in major adverse clinical events.

60. There was continued accrual of more major
adverse events in the control group than in
the LVEDP-guided therapy group beyond 30
days in context of CI AKI, suggested in other
studies as well
These findings emphasise the importance of
longer term follow-up CI AKI prevention trials

61. LVEDP guided iv saline administration is well
tolerated and could substantially reduce
chances of CI AKI and subsequent adverse
outcomes

62. Internal validation
Patient population :
comparable between the two groups except CHF
& PCI
Randomization ( blocks of 4)
Treatment :
higher volumes received by LVEDP group
Follow up:
10-15% excluded from primary analysis
(creatinine) but no loss on follow up
Outcomes
Long term outcomes measured

63. External validation
Patient population
Quite similar : high risk*
Treatment
short protocol- logistically feasible, ambulatory
procedures (longer protocols may be more effective)
Control group fluid rate- almost standard
Follow up
Can be done easily
Outcomes
CI AKI 25 %rise ( vs KDIGO)
Sustained loss / Progression to CKD

64. More aggressive volume expansion is not
suitable for all patients (ADHF, VHD)
LVEDP measurement is invasive and not
always available
Randomisation in blocks of four
Only partially blinded
CHF prevalence & PCI rate was different in
two groups