Contrast-induced Nephropathy — Just an Iatrogenic Kidney Disease?

Register or Login to View PDF Permissions
Permissions× For commercial reprint enquiries please contact Springer Healthcare:

For permissions and non-commercial reprint enquiries, please visit to start a request.

For author reprints, please email
Information image
Average (ratings)
No ratings
Your rating
Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

The Problem of Contrast-induced Nephropathy

Contrast-induced nephropathy (CIN) is an increasingly common cause of acute renal failure in both hospitalized patients and out-patients. The growth in contrast-enhanced imaging and interventional procedures is one cause of the increased incidence of CIN. An aging patient population, with more comorbidities such as reduced renal function, may be another reason for the higher incidence of CIN.

Definitions of CIN vary, but most investigators accept that a 25% or greater increase in serum creatinine, or decrease in calculated creatinine clearance in the appropriate clinical setting, defines CIN. The appropriate setting is:

  • exposure to intravenous or intra-arterial contrast;
  • a rise in creatinine within 24-48 hours of contrast exposure; and
  • the absence of other explanations for acute renal failure such as nephrotoxins, hypotension, urinary obstruction, or atheromatous emboli.

CIN is usually self-limited, with serum creatinine levels peaking in three to five days and gradually returning to baseline levels within seven to 10 days. Most CIN patients are non-oliguric and examination of the urinary sediment reveals only granular casts without red or white cells. Proteinuria is rarely present by dipstick testing. Urine sodium is often low, suggesting a prerenal physiology. A small percentage of patients with CIN (<5%) may require dialysis until renal function recovers.

Pathogenesis of CIN and Risk Factors

For the majority of patients with CIN, the transient rise in serum creatinine and eventual recovery to baseline mirrors the changes in renal function that are associated with volume depletion and pre-renal azotemia. This has led to important misunderstandings regarding the pathogenesis and prognosis associated with CIN. CIN represents a combination of toxic and ischemic injury to the kidney, predominately in the medulla. Decreases in medullary blood flow and medullary oxygen tension follow exposure to contrast. Increases in vasoconstrictor hormones, such as endothelin and adenosine, and loss of vasodilatory factors such as nitric oxide, may contribute to the vasoconstriction that reduces medullary blood flow. At the same time that medullary flow and oxygenation are reduced, an increase in sodium is delivered to the medullary tubules because of the osmotic effect of the contrast agent. The loop of Henle increases sodium reabsorption in response to this load (an oxygen-requiring process). The increase in oxygen requirements coupled with decreased oxygen availability results in ischemic injury.

Since only a minority of patients exposed to contrast media suffer this ischemic injury, there must be certain factors that predispose some individuals to this form of injury (see Table 1).

A variety of characteristics may predispose a patient to a higher incidence of CIN. Most importantly, pre-existing renal impairment is a risk factor - the worse the baseline renal function, the higher the risk. A general rule of thumb is that the risk is 10 times the serum creatinine. Diabetes, particularly with renal impairment, is another risk factor. Volume depletion, congestive heart failure, and the use of diuretics are also risk factors for CIN.

These factors both have renal physiology set toward vasoconstriction. Congestive heart failure, use of diuretics, and volume depletion are all associated with neurohumoral changes that predispose to renal sodium retention and vasoconstriction. Chronic kidney disease and diabetes are likewise associated with endothelial dysfunction and decreased vasodilatory responses. With the further burden of contrast-induced decreases in renal blood flow and increases in demand for oxygen, renal failure ensues.

Outcomes in Patients with CIN

The occurrence of CIN may tell us something about the state of the vasculature throughout the body. Levy et al. highlighted the increased in-hospital mortality seen in those who developed CIN versus those matched for renal function who did not. After adjusting for comorbidities, the risk of mortality was 5.5-fold higher in those who developed CIN. However, the increased mortality was related to sepsis, hemorrhage, and pulmonary complications, not to renal failure per se. Subsequent studies have confirmed the increase in in-hospital as well as one-year and five-year mortality in patients undergoing percutaneous coronary interventions who developed CIN. Clearly, mortality at one year cannot be directly related to the development of CIN. Rather, mortality in these patients was related to increased incidence of myocardial infarction. Of note, increased mortality has been noted primarily in those patients who had at least a 25% increase in creatinine following contrast exposure, supporting the clinical use of this definition of CIN.

In addition to short- and long-term implications for survival, CIN is associated with increased length of stay, hospital costs, and delay in subsequent procedures. Since the timing of CIN is predictable, many efforts have been made to prevent the occurrence of CIN.

Strategies for Prevention of CIN

Most strategies for prevention take advantage of the pathogenesis of the CIN. Preventing volume depletion and activation of renal vasoconstrictive forces is one of the most widely accepted strategies. Discontinuation of diuretic therapy and volume replacement with saline reduces the incidence of CIN by more than 50%.

In a prospective trial in high-risk patients, CIN occurred in 11% of those who received saline, 26% of those who received saline and mannitol, and 46% of those who received saline and furosemide (see Figure 1). The ideal volume replacement solution is in debate. The original studies used half normal saline but subsequent studies suggest superiority of normal saline or possibly isotonic sodium bicarbonate. In a recent study, the infusion of 3mL/kg/h x1 of an isotonic solution of sodium bicarbonate followed by 1mL/kg/h x6 was associated with a 2% incidence of CIN in high risk patients compared with 17% in a group randomized to normal saline.

Attempts to induce renal vasodilation with a variety of substances has been generally unsuccessful. Part of the problem may be the non-selectivity of the renal vasodilation. Most of the effect is in the cortex, which may, in effect, steal blood flow from the medullary, the primary site of injury. Dopamine, atrial natriuretic peptide, and fenoldopam (a dopamine agonist) have all failed to reduce the rate of CIN when subjected to multicenter, prospective, randomized trials. Single center trials with calcium channel blockers and adenosine antagonists have been somewhat successful but have not been subjected to rigorous multicenter testing.

N-acetylcysteine (Mucomyst®) is both a renal vasodilator and antioxidant.A number of single center trials have reported a reduction in the incidence of CIN with pretreatment the day before and the day of contrast exposure. An equal number of reports fail to show a benefit (26-30). The differences between studies may be related to dose (600 twice daily (bid) versus 1,200 bid), timing (day before versus day of), route of administration (oral versus intravenous), and other confounding factors such as the volume of contrast administered. Since acetylcysteine is inexpensive and has few side-effects, its use has been widespread despite the lack of compelling evidence in support of its benefit.