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Contrast-Induced Kidney Injury Risk Low in CKD, May Be

Preventable
Batya Swift Yasgur, MA, LSW

April 06, 2020

The risk of death and adverse kidney outcomes from contrast-associated acute kidney injury (CA-AKI) in patients with
chronic kidney disease (CKD) may be lower than previously thought, a new study suggests.

Investigators analyzed data from the Prevention of Serious Adverse Outcomes Following Angiography (PRESERVE) trial
(almost 4500 patients), and found that CA-AKI was associated with a low increased risk for death, need for dialysis, or
persistent kidney impairment at 90 days.

Moreover, CA-AKI did not mediate the relationship between baseline kidney function and the development of these serious
adverse outcomes.

"The key take-home message is that the incidence of clinically significant CA-AKI in patients with CKD who are undergoing
nonemergent angiography and who receive periprocedural isotonic intravenous fluid is very low," lead author Steven
Weisbord, MD, MSc, Veterans Affairs Pittsburgh Healthcare System, Pennsylvania, told theheart.org | Medscape
Cardiology.

The study was published online March 16 in the Journal of the American College of Cardiology.

A separate pilot study, published online March 11 in JACC Cardiovascular Interventions, showed that recombinant human
C1 esterase inhibitor (rhC1INH) — an agent used to treat hereditary angioedema — administered prior to elective coronary
angiography in patients with CKD attenuated the risk of increased urinary neutrophil gelatinase-associated lipocalcin
(NGAL), a biomarker for impaired kidney function.

It also reduced the spike in cystatin C in patients undergoing more invasive procedures.

"RhC1NH is a promising intervention to attenuate [contrast-induced] renal damage [following angiography] and may be
effective in a variety of settings," senior author Michael Osthoff, MD, senior consultant and head of clinical research, Division
of Internal Medicine, University Hospital Basel, Switzerland, told theheart.org | Medscape Cardiology.

Incomplete Picture

"The primary motivation for our study was our interest in understanding the nature of the relationship between acute kidney
injury following angiography and longer-term outcomes," said Weisbord, who is also a professor of medicine in the Renal-
Electrolyte Division at the University of Pittsburgh School of Medicine.

Previous research has shown a "substantially increased relative risk for serious outcomes with CA-AKI," including mortality,
stroke, myocardial infarction (MI), and/or end-stage kidney disease.

"One likely result of these studies…is that providers are less likely to perform contrast-enhanced procedures in patients with
CKD, due to concern for precipitating CA-AKI," the authors state.

The earlier research was limited by retrospective design, reliance on administrative data, and lack of assessment of whether
CA-AKI was a mediator or simply a marker for patients at heightened risk for serious adverse events.

"Consequently, the findings of these studies on which providers gauge the risk for CA-AKI and serious adverse sequelae
may paint an incomplete and/or inaccurate picture of the true risks," they note.

To clarify the issue, the researchers analyzed data on 4418 participants in the PRESERVE study, which evaluated pre-
angiography estimated glomerular filtration rate (eGFR) and tracked the development of CA-AKI on day 4 until the primary
endpoint of 90 days.

For the current study, the primary outcome was the composite endpoint of the PRESERVE trial, consisting of death, need
for dialysis, and/or persistent kidney impairment at 90 days.

The researchers also calculated the incidence of clinically significant CA-AKI and investigated whether it mediated an
association of baseline kidney function with 90-day outcome.

CA-AKI was defined as an increase in the serum creatinine of ≥ 0.5 mg/dL and/or ≥ 25% on assessments conducted
between days 3 and 5, compared with pre-angiography creatinine level.

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Covariates included demographic, laboratory, and clinical variables (eg, history of diabetes mellitus and MI) and treatment
intervention (sodium bicarbonate, sodium chloride, or N-acetylcysteine).

The patients were close to age 70 years and most were white; almost all (93.9%) were male.

No Need for Excessive Concern

The primary outcome occurred in 12.3% patients who experienced CA-AKI vs 3.5% patients who did not experience CA-AKI
(odds ratio [OR], 3.93; 95% confidence interval [CI], 2.82 - 5.49; P < .0001).

When the researchers adjusted for age, sex, urine albumin-to-creatinine ratio, diabetes, and MI, they found "no attenuation
of the strength of this association."

Additionally, CA-AKI was not found to mediate the association between baseline kidney function and the primary outcome;
in and of itself, pre-angiography eGFR was significantly associated with the development of CA-AKI (β-coefficient 0.0025;
95% CI, 0.0021 - 0.0029).

Pre-angiography eGFR and CA-AKI were both significantly associated with the primary outcome.

On the other hand, the indirect effect of pre-angiography eGFR on the primary outcome through CA-AKI was characterized
by an OR of 1.0061 (95% CI on bootstrap analyses, 1.0041 - 1.0086).

Thus, "the estimated proportion of the total effect of pre-angiography eGFR on the primary outcome mediated by CA-AKI
demonstrated that there was no mediation," the authors summarize.

"Our study had as a strength a large study population, all of whom had complete data collection and who were followed
prospectively for study outcomes, which greatly limited ascertainment biases and other limitations of retrospective studies,"
Weisbord said.

"Providers should typically perform clinically indicated angiographic procedures in these patients using appropriate
preventive care without undue excessive concern for causing AKI," he advised.

Not an "Innocent Bystander"

In an accompanying editorial, Harold L. Dauerman, MD, and Richard J. Solomon, MD, both of the Larner College of
Medicine, University of Vermont, Burlington, write that the "role of contrast in causing renal injury and adverse
consequences for patients remains unclear…we are not yet ready to conclude that CA-AKI is truly an innocent bystander."

They added that identification of patients at risk, appropriate fluid administration, and minimization of contrast dose "remain
important for now."

Commenting on this secondary analysis of PRESERVE trial data for theheart.org | Medscape Cardiology, Osthoff said that
the "risk of serious complications following the intra-arterial administration of contrast media is very low, and hence
angiographies should not be withheld in patients with impaired renal function."

However, Osthoff added, "although the overall risk is low, there is probably a subgroup of patients that may still benefit from
interventions aimed at protecting the kidneys during angiography, and future studies should focus on these highest risk
patients."

Inflammatory Pathways

Osthoff said he and his colleagues were motivated to conduct their study because interventions to prevent CA-AKI are
"scarce."

Experimental data suggest that inflammatory pathways — particularly the complement system — may mediate CA-AKI, he
noted.

"RhC1INH, a human plasma protein, is a powerful multi-action, multiple-target component that interferes with multiple
plasmatic cascades, including the complement system, and was shown to ameliorate renal injury by dampening the
inflammatory response," he explained.

"Hence, we were interested to investigate this promising compound in a pilot study in high-risk patients," he said.

The researchers conducted PROTECT (Prophylactic rhC1-inhibitor to prevent contrast-induced nephropathy trial), which
randomly assigned 77 patients with CKD (mean age 77 years, 70% male) to receive either placebo (n = 39) or rhC1INH (n =
38) before elective coronary angiography, and then 4 hours afterward.

Patients were required to have an estimated eGFR of ≤ 50 mL/min/1.732. They were also required to have at least 1
additional risk factor for CA-AKI (eg, diabetes mellitus, anemia, or congestive heart failure).
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The researchers used a modified intention-to-treat (mITT) model that included all participants who had received at least one
dose of study medication and underwent coronary angiography. A second analysis focused on the per-protocol (PP)
population, which consisted of patients fully complying with the trial protocol.

A post-hoc analysis focused on patients receiving a larger amount of contrast media and undergoing percutaneous coronary
intervention (PCI).

To ascertain the extent of kidney damage, peak change of urinary neutrophil gelatinase-associated lipocalcin (NGAL) — a
surrogate marker of kidney injury — was measured within 48 hours and constituted the primary outcome.

Favorable Safety Profile

Patients in the PP population showed a median peak change of urinary NGAL that was lower in the rhC1INH group than in
the placebo group (4.7 vs 22.5 ng/mL, P = .038). A similar change, however, was not seen in the mITT analysis (median 7.2
vs 22.5 ng/L, P = .119).

The post-hoc analysis revealed that in PCI patients who received a larger amount of contrast media, the median absolute
and relative peak change of urinary NGAL were significantly smaller in the rhC1INH group (1.8 vs 26.2 ng/mL, P = .039)
compared with the placebo group (11% vs 205%, P = .002).

No such difference was found in non-PCI patients.

Although the frequency of CA-AKI was comparable between the rhC1INH and placebo groups, the incidence of a cystatin C
increase of >10% within 24 hours was lower in the rhC1INH group (16% vs 33%, P = .045).

There was a similar distribution of adverse events between the 2 groups during 3-month follow-up.

"There was a lower incidence of a significant cystatin C increase, another marker of acute injury," Osthoff noted.

"Importantly, the safety profile was favorable in an elderly patient population with multiple comorbidities and polypharmacy,"
he said.

Intriguing and Reassuring

Commenting on the PROTECT study, Weisbord noted that it "was not powered to investigate efficacy."

Moreover, he continued, "It used a primary outcome that was a surrogate endpoint of unclear clinical significance."

However, in an accompanying editorial, Hitinder S. Gurm, MD, of the Division of Cardiovascular Medicine, University of
Michigan, Ann Arbor, described himself as "cautiously optimistic," calling the safety and efficacy signals in the study
"promising."

Osthoff stated, "The mechanism of action [of RhC1INH] is intriguing and its favorable safety profile in the current study is
reassuring, which is essential for the design of future trials in a similar patient population."

The study by Weisbord et al was funded by the Veterans Affairs Cooperative Studies Program and National Health and
Medical Research Council of Australia. Weisbord has consulted for Saghmos Therapeutics and Cytokinetics. Dauerman has
served as a consultant to Medtronic, Boston Scientific, Celacor, Abiomed, and Sonogenix; and has received research grants
from Medtronic and Boston Scientific. Dauerman has served as a consultant to Medtronic, Boston Scientific, Celacor,
Abiomed, and Sonogenix and has received research grants from Medtronic and Boston Scientific. Solomon is a consultant
for Sonogenix.

The study by Osthoff et al was supported by grants from Pharming Biotechnologies, the Department of Research of the
University of Basel, and the Foundation Machaon, Switzerland. Osthoff disclosed consulting fees from Pharming
Biotechnologies. Gurm reported consulting to Osprey Medical and receiving research funding from the National Institutes of
Health Centers for Accelerated Innovation and Blue Cross Blue Shield of Michigan.

J Am Coll Cardiol. Published online March 16, 2020. Abstract, Editorial

JACC Cardiovasc Interv. Published online March 11, 2020. Article, Editorial

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Cite this: Contrast-Induced Kidney Injury Risk Low in CKD, May Be Preventable - Medscape - Apr 06, 2020.

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