Contrast-induced nephropathy (CIN)

Contrast-induced nephropathy (CIN) is defined as the impairment of renal function—

measured as either a 25% increase in serum creatinine (SCr) from baseline or a 0.5 mg/dL
(44 µmol/L) increase in absolute SCr value—within 48-72 hours after intravenous contrast
administration.

Prevention and treatment

Prevention centers around avoiding volume depletion. This has led to trials and practices
using oral hydration, volume expansion with IV fluids and bicarbonate, and both holding and
using diuretics. Other prevention strategies include using alternate imaging methods,
minimizing amount of contrast, using iso-osmolar nonionic contrast agents, and
administration of the antioxidant acetylcysteine.
Treatment is mainly supportive and aimed at volume and electrolyte balance. Some patients
may require renal replacement therapy, but this need is usually transient.

Risk factors
Risk factors for CIN can be divided into patient-related, procedure-related, and contrast-
related factors (although the risk factors for CIN are still being identified and remain poorly
understood).
Patient-related risk factors are as follows:
 Age
 CKD
 Diabetes mellitus
 Hypertension
 Metabolic syndrome
 Anemia
 Multiple myeloma
 Hypoalbuminemia
 Renal transplant
 Hypovolemia and decreased effective circulating volumes - As evidenced by chronic
heart failure (CHF), an ejection fraction (EF) of less than 40%, hypotension, and intra-
aortic balloon counterpulsation (IABP) use
Procedure-related risk factors are as follows:
 Urgent versus elective
 Arterial versus venous
 Diagnostic versus therapeutic
Contrast-related risk factors are as follows:
 Volume of contrast
 Contrast characteristics, including osmolarity, ionicity, molecular structure, and
viscosity
The single most important patient-related risk factor is preexisting CKD, even more so than
diabetes mellitus. Patients with CKD in the setting of diabetes mellitus have a 4-fold increase
in the risk of CIN compared with patients without diabetes mellitus or preexisting CKD.
Risk stratification scoring systems
CIN is the result of a complex interplay of many of the above risk factors. The presence of 2
or more risk factors is additive, and the likelihood of CIN rises sharply as the number of risk
factors increases. Researchers have tried to quantify the contribution of each risk factor to the
ultimate outcome of CIN.
Risk stratification scoring systems have been devised to calculate an individual patient’s risk
of developing CIN. This has mostly been done in patients undergoing percutaneous coronary
intervention (PCI), especially those with preexisting risk factors. Mehran et al developed a
scoring system based on points awarded to each of the following multivariate predictors :
 Hypotension = 5 points
 Intra-aortic balloon pump (IABP) use = 5 points
 CHF = 5 points
 SCr >1.5 mg/dL = 4 points
 Age >75 years = 4 points
 Anemia = 3 points
 Diabetes mellitus = 3 points
 Contrast volume = 1 point for each 100 mL used
Risk categories by total calculated score, CIN rates, and requirements for dialysis were as
follows:
 Low risk (score of ≤5): CIN rate 7.5%, dialysis in 0.04%
 Moderate risk (score of 6-10): CIN rate 14%, dialysis in 0.12%
 High risk (score of 11-15): CIN rate 26.1%, dialysis in 1.09%,
 Very high risk (score of ≥16): CIN rate 57.3%, dialysis in 12.6%

Treatment

A number of other therapies for CIN have been investigated, including the following:
 Sodium bicarbonate
 N-acetylcysteine (NAC)
 Statins
 Ascorbic acid [31]
 The adenosine antagonists theophylline and aminophylline
 Vasodilators
 Forced diuresis
 Renal replacement therapy
 Prostaglandin E1

Hydration Therapy
The first study revealing the benefit of hydration in CIN prevention came from Solomon et
al. They also found forced diuresis to be inferior to hydration with 0.45% saline. Fluids with
different compositions and tonicity have since been studied, as well as the addition of
bicarbonate and mannitol.
Normal saline has been found to be superior to half-normal saline in terms of its enhanced
ability to produce intravascular volume expansion. It also increases delivery of sodium to the
distal nephron, prevents renin-angiotensin activation, and thus maintains increased renal
blood flow. In terms of route of administration, oral fluids, while beneficial, have not been
considered as effective as intravenous hydration.
Statins
Statins are widely used in coronary artery disease (CAD) for their pleiotropic effects
(favorable effects on endothelin and thrombus formation, plaque stabilization, and anti-
inflammatory properties), and it was believed that, given the vascular nature of CIN, they
might have similar renoprotective effects. Iniital data for statin use were retrospective and
anecdotal, and were taken mostly from patients already on statins who underwent
percutaneous coronary intervention (PCI). Subsequently, a meta-analysis of prospective
controlled studies found a statistically significant reduction of CIN incidence in patients
pretreated with high-dose statins before the procedure (odds ratio [OR], 0.45; 95%
confidence interval, 0.34-0.58; P < 0.0001).

Bicarbonate Therapy
Bicarbonate therapy alkalinizes the renal tubular fluid and thus prevents free radical injury. In
the Harber-Weiss reaction, which is activated in an acidic environment, hydrogen peroxide
and an oxygen ion (from superoxide) react to form a hydroxide ion, all agents of free radical
injury. Bicarbonate, by alkalinizing the environment, slows down that reaction. It also
scavenges reactive oxygen species (ROS) from nitric oxide, such as peroxynitrite.
Bicarbonate protocols most often include infusion of sodium bicarbonate at the rate of 3
mL/kg/hour an hour before the procedure, continued at 1 mL/kg/hour for 6 hours afterward.
Some investigators have used 1 mL/kg/hour for 24 hours, starting 12 hours before the
procedure. The exact duration, however, remains a matter of debate. Hydration with sodium
bicarbonate has been found by some researchers to be more protective than normal saline
alone.

N-acetylcysteine
NAC is acetylated L-cysteine, an amino acid. Its sulfhydryl groups make it an excellent
antioxidant and scavenger of free oxygen radicals. It also enhances the vasodilatory
properties of nitric oxide.
In a systematic review and meta-analysis of 61 randomized controlled trials that included
11,480 patients, Xu et al determined that NAC supplementation was associated with a
significant decrease in CIN risk and blood creatinine level, but not with a reduction in
mortality or nephropathy requiring dialysis. In addition, NAC supplementation did not reduce
the risk of CIN in patients with diabetes
Renal Replacement Therapy
Fewer than 1% of patients with CIN ultimately go on to require dialysis, the number being
slightly higher in patients with underlying renal impairment (3.1%) and in those undergoing
primary percutaneous coronary intervention (PCI) for myocardial infarction (3%). However,
in patients with diabetes and severe renal failure, the rate of dialysis can be as high as 12%.
Patients who get dialyzed do considerably worse, with in-hospital mortality rates of 35.7%
(compared with 7.1% in the nondialysis group) and a 2-year survival rate of only 19%.
Other Therapies
Ascorbic acid, which has antioxidant properties, was studied for its ability to counter the
effect of free radicals and reactive oxygen species. One study found that oral ascorbic acid
administered in a 3-g dose preprocedure and two 2-g doses postprocedure was associated
with a 62% risk reduction in CIN incidence.
Theophylline and aminophylline are adenosine antagonists that counteract the intrarenal
vasoconstrictor and tubuloglomerular feedback effects of adenosine. They have been found to
have a statistically significant effect in preventing CIN in high-risk patients. However, their
use is limited by their narrow therapeutic window and adverse effects profile.
Vasodilators, such as calcium channel blockers, dopamine/fenoldopam, atrial natriuretic
peptide, and L-arginine, all with different mechanisms of action, have a favorable effect on
renal hemodynamics. However, their use for CIN prevention has not been borne out by most
controlled trials, and they are not routinely recommended at this point.
Forced diuresis with furosemide and mannitol was studied in the hope that this procedure
would dilute CM within the tubular lumen and enhance their excretion. Furosemide and
mannitol in fact worsen CIN by causing dehydration in patients who may already have
intravascular volume depletion. Their use at this time is discouraged.