Prevention of contrast-induced acute kidney injury induced by angiography
CONTRAST NEPHROPATHY
Prevention of contrast-induced
acute kidney injury induced by angiography
Abbreviations:
o
Aa:
ascorbic acid.
o
AC: acetyl
cysteine.
o
ACC/AHA:
American College of Cardiology/American Heart Association.
o
ACEi: angiotensin-converting
enzyme inhibitors.
o
AKI: Acute kidney
injury.
o
AMI: acute
myocardial infarction.
o
ANP: Atrial
natriuretic peptide.
o
APO: pulmonary
edema.
o
ARBs: angiotensin
receptor blockers.
o
ATN: acute tubular
necrosis.
o
C.I.: contraindications.
o
CA-AKI: Contrast-associated
AKI.
o
CIN: contrast-induced
nephropathy.
o
CKD: chronic
kidney disease.
o
Dc Np: Diabetic
nephropathy
o
DD: differential
diagnosis.
o
eGFR:
estimated GFR.
o
HDX: hemodialysis.
o
HF/HDX: hemofiltration
or hemodialysis
o
LVEDP: left
ventricular end-diastolic pressure.
o
MM: multiple
myeloma.
o
MR: mortality.
o
Na+HCO3: Sodium bicarbonates.
o
NSAIDs:
nonsteroidal anti-inflammatory agents.
o
PCI:
percutaneous coronary intervention.
o
PCIs:
percutaneous coronary interventions.
o
Prox: prophylactic
o
RCT: randomized
controlled trial.
o
RI: renal
impairment.
o
RIPC: ischemic
preconditioning.
o
RRT: renal
replacement therapy.
o
RRT: renal
replacement therapy.
o
Sln: Saline.
o
Sn & Sm: signs and symptoms.
o
USS: Ultrasound
scanning.
o
UO: urine
output.
o
VC: vasoconstriction.
o
ACR: albumin-to-Cr ratio
AKI that can be observed
shortly after contrast media could or could not be attributed to contrast administration.
"Contrast-associated AKI (CA-AKI)"
is a general term referring to AKI seen shortly after iodinated material use and may
or may not be a direct causative related to contrast material. CI-AKI," previously named CIN," is a more specific term referring
to the CA-AKI
diagnosed after a thorough clinical assessment, to be causally attributed
to contrast administration. This term “CA-AKI” is coincident to current clinical assessment for
other possible AKI etiology has not been engaged or other causes of AKI cannot
be currently excluded. Moreover, CA-AKI can be also referred to rising SCr (or drop in eGFR)
after contrast media in research work.
Major clinical criteria:
o
Rising SCr (mild) generally
seen within 24-48 h. after
iodinated contrast.
o
Mostly non-oliguric. Oliguria may be seen with
severe AKI
or underlying CKD.
o
Urinary sediment: classic ATN: muddy brown granular- epithelial cell
cast-free tubular epithelial cell.
CI-AKI ptn should be subjected to a
full detailed history & physical testing with a urine microscopy for urinary sediment to
recognize findings suggesting an alternate etiology. Oliguric ptns with severe AKI (requiring RRT)
may be amenable to have an alternate causes of AKI.
An USS is
not typically mandated, despite it may be required to exclude obstructive
causes of AKI especially if Dgx of CI-AKI still uncertain (e.g., oliguria, severe
AKI). Proteinuria in CI-AKI is typically lacking or mild (unless ptn
proteinuric at background). However, the finding of albuminuria (via dipstick
or ACR) does not exclude CI-AKI. CI-AKI
is a clinical
Dgx primarily based on TWO criteria:
o
Rising SCr upon
1st 24-48 h.s after
contrast.
o
Reasonably excluded other factors of AKI
Renal biopsy is generally not required for Dgx of CI-AKI, as ATN
pathology is usually focal & non-specific, in addition CI-AKI is short termed one. However, as with USS, biopsy may be rarely indicated to exclude
other causes of AKI if Dgx of CI-AKI
still uncertain.
DD includes, kidney
atheroemboli (with intra-arterial contrast testing), ischemic ATN, acute interstitial nephritis, and pre-renal
alterations induced by adding of diuretics, ACEi
or ARBs after contrast study. As many
AKI etiologies, the management of CI-AKI is mainly supportive including removal
and holding other possible kidney insults, hemodynamic & electrolyte evaluation
and management, proper dose adjusting for the degree of decline
in GFR, and, with severely deteriorated
kidney function, management of uremic Sn & Sm.
Ptns with CI-AKI usually expressing a
mild decline in GFR that is mostly
improving within 3-7
days. Most ptns resumed their baseline eGFR.
DX is rarely indicated for CI-AKI.
Despite CI-AKI is mostly reversible,
it can be complicated by adverse outcome. The reported sequelae of CI-AKI is much robust with arterially administrated route
as compared to the venous route. This difference can be attributed to the difference
in ptn populations (ptns requiring arterial
contrast are more likely expressing
many co-morbid diseases that augment the likelihood of AKI) or the difference in nephrotoxicity of intra-arterial contrast is more robust. Prevention of arterial contrast-induced CI-AKI will
be covered here.
EPIDEMIOLOGY
The observed incidence of CI-AKI is
variable affected by AKI definition,
the presence/absence of risk factor(s) (underlying CKD),
magnitude and type of used agents, and the type of radiologic testing. Ptns with
no risk factors (CKD in particular),
their risk of CI-AKI is unnoticed (i.e.,
≤1 %). Whilst
others with risk factors (particularly DM & CKD),
their reported risk after coronary angiography
with or with no intervention = 10-30 %.
Major risk factors: are either ptns
related or procedure related.
Ptn-related factors for CI-AKI include:
1)
CKD (particularly Dc Np),
2)
Diminished kidney
perfusion from HF,
3)
Hypovolemic/hemodynamic
unstable ptns,
4)
MM (Myeloma kidney).
Procedure-related factors include:
1)
Dye dosage,
2)
Type of contrast
agents, &
3)
Specified procedure
(intra-arterial
vs IV & interventional vs diagnostic angio-study).
Arterial study of contrast that is of a higher
risk than venous ones.
1)
CKD: Incidence of CI-AKI is higher in CKD and increasing with the higher intensity of renal
dysfunction. The increasing risk is likely continues with the dropping in eGFR. However, the threshold of GFR at which the risk is more evident still
uncertain. Study: estimating the risk with mild/moderate CKD, 289 ptns with eGFR:
30-59 mL/min/1.73 m2, % AKI = 4.2 % after intra-arterial contrast.
Severe CKD (= eGFR <30 mL/min/1.73 m2) were excluded. Study:
124 ptns with SCr ≥3.0
mg/dL (265 mmol/L) (average eGFR <30 mL/min/1.73 m2), % AKI after PCIs = 31 %. Proteinuria augment the risk more with declined eGFR. Prospective study: 70 CKD ptns (CKD = eGFR
<60 mL/min/m2 and/or proteinuria),
AKI observed
after angiography in 62
% of ptns + proteinuria >1 g./d. vs 21 % in those with proteinuria <1 g./d.
2)
Dc Np + low eGFR: Dc ptns are at increasing risk as compared to non- Dc ptns. RCT: 250 ptns with SCr >1.5 mg/dL (133 micromol/L), a high % of AKI
was seen among Dc ptns as compared to non- Dc ptns (33 vs 12 %, resp). Ptns with normal kidney function, 2 studies:
DM does not augment the risk of CI-AKI. RCT:
341 ptns with SCr ≤1.5 mg/dL (133 mmol/L): no difference in %
of CI-AKI between Dc &
non- Dc ptns.
Review: 1826 ptns, DX-requiring AKI seen after
interventional coronary angiography in 19.5 % of Dc ptns vs 12.8 % of non-Dc CKD ptns; No ptn with CrCl >47 mL/min developed DX-requiring AKI.
3)
Dose/type
of contrast media: Low dose (<125 mL) of contrast is safe, despite not entirely
free of risk. Minimal
amount of contrast (<10 mL) have been safely tried with sever kidney disease to examine A/V fistula.
However, Dc
ptns with SCr >5 mg/dL (440 micromol/L) may be at increased
risk for as little as 20-30
mL of contrast. Type of contrast media can impact the risk. Contrast media
could be either ionic or nonionic with
varied osmolality. Older agents (1st generation) were ionic/hyperosmolal
compared to plasma (1400-1800
mosmol/kg) and rarely used
today and more nephrotoxic as compared to current agents.
Currently used agents:
o
Low-osmolal agents: with lowered
osmolality < 1st generation radiocontrast agents but still higher osmolality (500-850 mosmol/kg) as compared to
plasma. Commonly used low-osmolal agents including non-ionic agents (iohexol, ioversol & iopamidol) and the ionic
agent, ioxaglate.
o
Iso-osmolal agents: Only one iso-osmolal agent (iodixanol) is
available. It is non-ionic &
iso-osmolal with plasma (290 mosmol/kg). The lowered risk of new agents is likely attributed to the {lowered
osmolality + lack of charge}. The exact role of charge vs osmolality are difficult to recognize as most reports
compared non-ionic low-osmolal agents vs ionic hyperosmolal media. However, a benefit of low osmolality was observed in one study: ionic
low-osmolal ioxaglate is less toxic compared to ionic
hyperosmolal media (1500-1800 mosmol/kg).
Among new agents, the iso-osmolal agent iodixanol
has been supposed to show a lowered risk of AKI than low-osmolal
agents, especially iohexol, among high-risk ptns. Meta-analysis:
25 RCT comparing
iodixanol with a diverse g. of
low-osmolal media (72 % with RI or DM)
reported a moderate decline in risk of AKI with iodixanol. There was no difference in the eventual risks
for RRT, CVS events, or death. It is possible that iohexol carries a higher risk of AKI compared with non-iohexol low
osmolal media. Trial: comparing iodixanol & iohexol in 129
high-risk Dcs
& CKD (mean SCr 1.5 mg/dL [133 micromol/L]) undergoing
angiography, iodixanol showed
a lowered incidence of AKI (3 vs 26 % with iohexol). However, 3 trials that compared iodixanol with 2 other non-ionic low-osmolal contrast media
(ioversol & iopamidol) showed no difference between g. in the rate
of AKI. Moreover, a meta-analysis of
16 RCT suggested
that iodixanol showed lowered risk in CKD ptns receiving
contrast if compared with iohexol but not if compared with other non-ionic low-osmolal
contrast media. These data suggest that the benefit of iodixanol as compared to iohexol may denotes
a unique nephrotoxic impact of iohexol.
Specific radiologic procedure: The highest observed
risk for AKI
can be seen with (rather than diagnostic)
coronary angiography (esp. interventional AMI).
This could be attributed to the higher volume of agents used in interventional maneuvers + hemodynamic
instability seen with AMI. Most reports have shown quite lowed risk of AKI observed with contrast CT scan (i.e., IV.
contrast) is, even with the presence of CKD.
Other risk factors: may include hyperglycemia &
the use of ACEi/ARBs. Hyperglycemia may augment the risk for CI-AKI independently
of comorbid DM. Study:
adjusted risk of AKI after
angiography increasingly higher with elevated glucose with no diagnosed DM. No rise in glucose-associated risk with
established DM. The impact of ACEi and/or
ARBs on the incidence of CI-AKI is not
clear. Retrospective study:
5299 ptns proceed to percutaneous intervention, ACEi
or ARB use
contributes to AKI evolution. However,
RCT: 220 ptns, eGFR of 15-60 mL/min/1.73 m2: no difference in
the rate of CI-AKI development between ACEi and/or ARBs
users before angiography and the cohort with similar decline in eGFR but
not on ACEi and/or ARBs. Moreover, it is not obvious whether ACEi/ARB
withdrawal before angiography will provide any protective benefit.
PREVENTION: measures should
be focused on ptns receiving intra-arterial
contrast. It is crucial to consider that many trials evaluating preventive
measures have used small, transient rise in SCr as endpoint (e.g., ≥0.5 mg/dL [44.2
micromol/L] or ≥25-50 % above
baseline). However, trials suggesting that CIN,
considering this attitude, is accompanied with significant in-hospital as well
as long-term MR.
Risk ptns:
o
eGFR <60 mL/min/1.73 m2 + significant
proteinuria (= albuminuria
>300 mg/d,
corresponding to proteinuria > 500
mg/d).
o
eGFR <60 mL/min/1.73 m2 + co-morbid DM,
HF, liver
failure, or MM.
o
eGFR <45 mL/min/1.73/m2 even with no proteinuria
or any other co-morbidity.
o
eGFR
<45 mL/min/1.73 m2 + proteinuria +
DM or other co-morbidities &
o
eGFR <30 mL/min/1.73 m2 considered at highest risk for
all ptns.
Preventive measures:
[1] Avoid volume
depletion & NSAIDs: ptns
receiving intra-arterial contrast should avoid dehydration and volume
depletion. Withhold NSAIDs 24-48 h.s prior
to the study. Both volume depletion & NSAIDs
can augment renal VC that trigger the
risk of CI-AKI. No withhold ACEi & ARBs
is advised. Data are insufficient to assure a benefit of ACEi/ARBs
withdrawal and there is risk with resultant HT.
[2] Dose & type of contrast agent: administration
of the lowest effective possible dosing of contrast is advised with avoiding
repeated close procedures (48-72 hs). Iso-osmolal agent, iodixanol,
or non-ionic low-osmolal media, e.g. iopamidol or ioversol,
rather than iohexol.
Do not inject high-osmolal media (1400-1800 mosmol/kg). Non-ionic,
iso- or low-osmolal
media are safer than ionic high-osmolal media. The
iso-osmolal, iodixanol,
may be safer than iohexol among risky
ptns but shows only a slight, if any, benefit compared to other non-ionic
low-osmolal media. The 2012 KDIGO guidelines recommended low-osmolal or
iso-osmolal rather than higher-osmolal media but they found no real supporting
evidence to recommend either low-
vs iso-osmolal contrast.
[3] Fluids:
ALL at-risk ptns proceeding to intra-arterial contrast, if no C.I. to volume expansion > IV isotonic Saline before to & several h.s after the contrast study.
A preferred protocol is following:
o
Outptns: 3 mL/kg over one h. prior to the procedure and 1-1.5 mL/kg/h during and for 4-6 h.s after procedure,
at least 6 mL/kg post-contrast.
o
In-ptns: 1 mL/kg/h. for 6 -12 h. pre-contrast,
intra-contrast, and for 6-12 h.s after the procedure.
o
Rationale: IV volume expansion
prior to procedure for high risk ptns is the
standard care despite lack of RCT.
Further trials comparing prox fluids to no
fluid are needed. Few RCT tested effects of IV fluids with no other
interventions (e.g., forced diuresis). 3 RCT showed benefit, but of limited values:
2 trials: 408 &
216 ptns with AMI performing PCI,
with mostly normal renal profile, IV Sln decreased the risk of CI-AKI as compared to no Sln. Trial: in-hospital MR was
lowered with IV Sln (2.8 vs 9.3 %).
Rates of ventricular arrhythmias, APO,
DX, mechanical ventilation were lower
in ptns receiving Sln. However, in
both trials, prevalence of AKI that decreased
with fluid, may have been attributed to limitation in episodic hypotension
via IV hydration rather than a direct protective anti-CI-AKI impact on high-risk ptns.
Non-placebo-controlled RCT (POSEIDON) showed indirect
evidence of a beneficial dose-response
of fluid optimization. An aggressive fluid hydration protocol guided by LVEDP was compared to standard IV fluid, eGFR <60 mL/min/1.73 m2. All ptns received IV
isotonic Sln
3 mL/kg for one h. before
cardiac catheterization. LVEDP was assessed in all ptns prior to contrast. In
the LVEDP-guided g., ptns received:
o
5 mL/kg/h if LVEDP = <
13 mmHg,
o
3 mL/Kg/h if LVEDP = 13-18 mmHg, &
o
1.5 mL/Kg/h. if LVEDP = >
18 mmHg.
o
The control g.
received 1.5 mL/kg/h.
Both g.s received IV fluid throughout the
procedure & 4 h.s
afterward. CI-AKI observed less
frequently in the LVEDP g. as compared to control.
Isotonic saline: Isotonic Sln appears to
be better than more hypotonic fluids (i.e., 1/2 isotonic saline). RCT:
1620 ptns, compared with 1/2 -isotonic Sln,
isotonic Sln decreased the risk of CI-AKI.
Impact of isotonic saline was higher in Dcs (5.5 % vs 0) & ptns given >250 mL of contrast media (3
vs 0 %). However, there was no observed difference with significant renal impairment
(SCr >1.6 mg/dL [>141 micromol/L]). It is vital
limitation as ptns with RI who will be at higher risk for CI-AKI, this trial was underpowered in the
item of sub-g.; so, a minimal benefit of Sln may have been missing here.
Saline vs bicarbonate: We recommend Sln rather than
bicarbonate. Both are effective, but Na+HCO3 gives no more benefit
to Sln, with the need to be
compounded, and is more costly. Na+HCO3 has been compared
with isotonic Sln in a number of RCT &
meta-analyses with conflicting data. The most
informative RCT:
4993 high-risk ptns with planned angio-study: both therapies showed similar
outcomes. All ptns with stable renal function, eGFR 15-44.9
mL/min/1.73 m2 with or without DM or eGFR 45-59.9
mL/min with DM. 81% were diabetics. Ptns received 1.26 % Na+HCO3
or 0.9 % Na+
Cl + either oral AC (1200 mg one h. before & one h. after angio, then twice/d./4
d.) or placebo capsules. Hydration
was as follows of 1-3 mL/kg/h/1-12h before angio
(total 3-12 mL/kg), 1-1.5 mL/kg/h. during angio
& 3 mL/kg/h./2-12 h. after angio
(total 6-12 mL/kg after angio). Similar rates of AKI, need
for DX at 90
d.s or persistent RI by 90 d.s & death rate in Na+HCO3 & Sln g.
Oral salt loading: We do not use
oral salt loading in place of IV volume expansion. The benefit of oral
hydration or salt loading for the prevention of CI-AKI is not known. However, 2 small trials
have suggested that oral
salt may provide a benefit comparable with IV fluids.
Acetylcysteine (AC): AC not given prior to angio. Meta-analyses: AC have shown variable results. Generally, moderate
benefits were observed in meta-analyses. The largest RCT, did NOT show better outcome with oral AC in 4993 high-risk ptns
with planned angio. Benefit of IV AC still
uncertain, one trial: 7 % of ptns receiving high dosages IV AC experienced anaphylactoid
reaction.
UNPROVED AGENTS: RIPC, ANP, statins, & Aa.
Remote ischemic pre-conditioning: RIPC is a
method by which the deliberate induction of transient non-lethal ischemia of an
organ protects against subsequent ischemic injury of another organ. Some, but
not all, studies have suggested that RIPC prior to cardiac
surgery protects against AKI. RIPC may also protect against CI-AKI. These data need to be confirmed in
larger RCT
before RIPC can be advised as a preventive measure for CI-AKI.
Prox hemofiltration
& HDX: Routine HF/HDX for
CI-AKI prevention
in CKD is not advised. A 2012 meta-analysis including 8 studies of HDX & 3 studies of HF/HDF showed No benefit of RRT. There’s no indication for prox DX to
prevent volume overload related to IV contrast in DX-dependent
ptns.
Furthermore, there are no studies supporting
immediate DX
after intravascular contrast studies to preserve residual kidney
function or to limit the risk of allergic or toxic reactions to contrast media
in HDX ptns. Whereas some clinicians
try to perform a HDX within 24-36 h.s after intravascular contrast media exposure,
others wait 48-72 hs, until
the next scheduled HDX. The latter
approach is advised, except in HDX ptns who are significantly volume overloaded at
the time of contrast study. Withholding ACEi/ARBs prior to angio-study is not
recommended. Some studies have suggested that ptns on an ACEi/ARBs are
at higher risk for CI-AKI as compared to ptns who are not.
However, it is not clear whether holding or
withdrawing an ACEi and/or ARB prior to angio-studies provides any benefit. Study:
220 ptns who were on ACEi or ARBs with an eGFR
of 15-59 mL/min/1.73 m2
were assigned before
angiography to either an ACEI/ARB withdrawal
g., in which ACEi/ARB were stopped 24 h. before the procedure, or to a
control g., in which ACEi/ARB were continued. There was no significant
difference in the incidence of CI-AKI between ptns having ACEi/ARB withdrawn
and those who did not. The issue of whether to hold ACEi/ARBs prior to contrast study is not resolved, and
further studies have been required.
Statins: statins administration
totally not advised for the prevention of CI-AKI.
A possible exception is ptns who are likely to be started on statins prior to
discharge, such as those with AMI,
among whom it’s reasonable to start statin prior to angiography.
Some studies suggested: statins may reduce
the risk. A meta-analysis of 8 studies (n = 5024) did not show a conclusive benefit of
statins plus IV Sln compared with Sln alone. However, analysis of 5 studies (n = 1477) revealed that statins
given with AC & IV Sln reduced
the risk of CI-AKI compared with AC & IV Sln alone.
Most of the statin studies were performed in relatively low-risk ptns. Moreover,
some reports suggest that acute administration of rosuvastatin is
associated with a rise in normal eGFR.
Statins desrve more workup for CIN
prophylaxis.
Diuretics: routine prox diuretics
or mannitol
for prevention of AKI is not
advised. These medications seem to be not beneficial for CI-AKI prox. However, diuretics may be provided
to manage volume overload.
It’s possible that forced
diuresis can help in AKI prevention if volume depletion can be prevented as shown in
studies utilizing the proprietary of fluid control
devices matching fluid repletion
to UO. Forced diuresis + matched
volume replacement can decline the possibility of AKI after angiography as compared to overnight
hydration. The potential benefit of the
fluid managing devices is that volume repletion & UO are hourly
controlled more than the conventional hydration protocols with no added risk of
volume overload. On the other hand, forced diuresis of high-volume has its
sequelae, even with application of the well-matched volume repletion. Volume
overload may be developed if isotonic Sln have been administrated to replace urine that is
after loop diuretics, usually of
tonicity of ½ normal Sln.
One trial: the raised
intravascular volume may be sufficient to augment the eGFR in ptns
commencing forced diuresis. Moreover, forced diuresis may precipitate arrhythmia
via electrolyte alterations e.g., hypokalemia can be complicated in susceptible
ptns.
Others: oral Na+ citrate, ANP, Aa, trimetazidine, VC inhibitors, and diuretics:
o
Oral Na+ citrate: One RCT: benefit of oral Na+ citrate (5 g/200 mL water) one h.
before & 4 hs after angio-study. Risk of CI-AKI was lowered with ptns receiving oral citrate as compared
to placebo (need to be confirmed).
o
ANP (anaritide): beneficial in animals, but NOT in
humans- for CI-AKI prox.
o
Ascorbic acid (Aa): Data are sparse about Aa for CI-AKI prox.
One RCT: proved benefit of Aa
in CIN prox, but another larger trial:
No added benefit to a prox isotonic Sln + Aa: in risky ptns. Meta-analysis: 6 trials:
No benefit of Aa.
o
Trimetazidine: cellular anti-ischemic agent additional
protection to isotonic Sln from CI-AKI in a small, prospective trial. Further work
up is warranted.
o VC Inhibitors: Many agents preventing VC, e.g., theophylline/aminophylline, captopril, PG E, low-dose dopamine, & fenoldopam, have been tried for CI-AKI prox, some but not all, trial prove risk reduction.
PROGNOSIS CI-AKI is
mostly reversible; eGFR may recover in 5-10 days. However, risky ptns with severe basal
decline in eGFR, the SCr may NOT recover to its previous
baseline. Even if SCr returned to baseline,
the evolution of CI-AKI can be associated with short- & long-term untoward
impacts. However, there’re NO current RCT with
proved specific interventions preventing AKI, decreasing MR or protecting from the expected serious CVS events.
COMMENTS