By: Stanley Goldfarb, MD, FACP, FASN, FCPP
In recent years, concerns about nephrotoxicity associated with high-osmolality contrast media (HOCM) have led to more widespread use of low- and iso-osmolality contrast agents in diagnostic imaging procedures. Those concerns have largely focused on contrast-induced nephropathy (CIN), the commonest and most important complication of the use of iodinated radiocontrast material. CIN has been variably defined as a condition characterized by kidney dysfunction following exposure to radioiodinated contrast media when no other explanation such as hypotension or sepsis can be implicated. The most common definition of CIN is a rise in serum creatinine (SCr) by 25% above baseline or an absolute increase of 0.5 mg/dl. However, recent observations have called into question the specificity of the diagnosis, as up to 20% of patients who are hospitalized with cardiac disease and who never receive contrast media may also have a spontaneous rise in SCr equal to that seen in patients diagnosed with CIN.[2,3] Nonetheless, since SCr is the only currently available measure of renal function, clinicians must employ the standard of an unexplained rise in SCr following contrast administration as evidence of CIN.
Mechanism of CIN
CIN is thought to result from ischemic injury to the kidney, specifically in the renal medulla, an area that is particularly sensitive to ischemic injury due to the very low oxygen tension in this region (15-20 mm Hg). The renal medulla is involved in solute accumulation in order to permit urinary concentration to occur; minimal blood flow is required to prevent dissipation of the medullary solute gradient. The consequence of minimal blood flow is very low oxygen tension.
Several experimental studies have demonstrated the medullary vasoconstriction that results from the administration of contrast agents. Those studies suggest that medullary ischemia is the likeliest mechanism of ischemic injury and the subsequent rise in SCr.
Risk Factors for CIN
While contrast agents may induce medullary ischemia in any subject, only certain individuals are at risk for CIN. The patients at greatest risk are those with chronic kidney disease (CKD), particularly CKD due to diabetic nephropathy. Others at increased risk include individuals with poor cardiac function, patients with underlying extracellular fluid volume depletion, and those receiving drugs that compromise renal blood flow. Notably, many clinical studies of CIN have failed to include adequate numbers of high-risk patients to allow sufficient power to detect differences in outcome.
Other risk factors have been proposed including patient age, dose of contrast agent, poor cardiac function, multiple exposures to contrast agents over a brief duration, use of pharmacologic agents that tend to cause renal vasoconstriction, extracellular volume depletion, and certain diseases such as multiple myeloma.
Recent studies suggest that very large doses of contrast media may increase the risk of CIN, and that there is likely a low dose that does not convey such a risk. Studies in patients at very advanced stages of CKD in whom contrast is administered to assess vascular access pre-dialysis have shown that kidney function for these high-risk patients does not decline if less than 20 ml of contrast agents are infused with the venography.
Clinical Assessment of Risk of CIN
Assessment of renal function depends on measuring and interpreting the SCr level. Creatinine is an organic base that is produced in the non-enzymatic breakdown of creatine released from muscle. Creatinine excretion via renal filtration allows its plasma level to be proportional to the glomerular filtration rate (GFR). However, the SCr level is also a function of the rate of creatinine production, which is reduced in older individuals. Consequently, plasma creatinine is lower at any level of renal function in many older individuals than in younger ones. This has led to the use of formulae that attempt to correct for creatinine production by factoring plasma creatinine by age, ethnicity, and gender, each of which can influence creatinine production.
While the use of such formulae seems rational, it has been disputed by experts who point out that normal aging is associated with a decline in GFR.[8,9] Yet this approach has placed many older individuals who are otherwise normal in a category of stage 3 CKD. Unfortunately, it is not clear that an elderly individual with an estimated GFR (eGFR) less than 60 ml/min — a criterion used in most studies to define CKD — actually has a form of renal disease.
Moreover, it has been suggested that approximately 50% of patients with an eGFR of 60 ml/min, as derived from the Modification of Diet in Renal Disease (MDRD) formula, actually have a true GFR substantially above 60 ml/min, as determined by the insulin clearance test. This too suggests that most clinical trials of CIN are underpowered if they use 60 ml/min as a criterion for CKD.
For clinical purposes, it would appear that a lower eGFR cutoff of 45 ml/min, or an actual elevation in SCr above the normal range, would be an appropriate criterion to identify patients with CKD and increased risk of CIN.
Strategies to Minimize the Risk of CIN
Three main approaches exist to reduce the risk of CIN: extracellular fluid volume expansion (also called hydration), prophylactic use of pharmacologic agents such as N-acetylcysteine, and use of contrast agents with a greater safety profile.
Volume expansion: Since the likeliest cause of CIN is induction of renal ischemia, expansion of the extracellular volume — a maneuver known to enhance renal blood flow and combat ischemia — is a crucial factor in any strategy to prevent CIN. Unfortunately, volume expansion usually requires intravenous administration of saline-containing fluids, which can be time-consuming and difficult to perform in outpatient settings. Most studies have recommended a volume infusion rate of isotonic saline at 1ml/kg/hr for 6 hours prior to and following contrast administration. Recently, Merten and colleagues proposed the infusion of isotonic sodium bicarbonate solution at a rate of 3 ml/kg/hr for one hour and a continuation of the protocol as 1 ml/kg/hr for an additional 6 hours following contrast administration. This has only been modestly successful compared to isotonic saline infusions, as reflected in several conflicting meta-analyses.[11,12] What is crucial is that some form of volume expansion be used in sufficient doses to raise renal blood flow. A rise in urine flow rate is the best clinical evidence that volume infusions have achieved the goal of raising renal blood flow.
N-acetylcysteine (NAC): This agent has been used for several years as prophylaxis for CIN following the observation by Tepel and colleagues that relatively small doses of oral NAC dramatically reduced the risk of CIN in patients undergoing computed tomography (CT) studies. The rationale for its use derived from the theory that renal ischemia leads to generation of oxygen free radicals that damage renal cell membranes. NAC acts to reduce the level of these oxygen free radicals. Unfortunately, multiple follow-up studies have failed to consistently confirm the benefits of NAC.[14,15] It continues to be widely used despite this very mixed experience. Perhaps its low cost and apparent lack of side effects have encouraged clinicians to include NAC in CIN prophylaxis, although it should not be used as the sole prophylactic agent, and it should always be used as an adjunct to volume expansion.
Choice of contrast agent: In 1995 the Iohexol Cooperative Study, a very large prospective trial of HOCM versus low-osmolality contrast media (LOCM) in patients undergoing diagnostic cardiac catheterization, clearly showed that the LOCM agent, iohexol, compared to the HOCM diatrizoate, conveyed a substantial reduction in CIN risk, particularly in high-risk patients (defined as those with a baseline SCr value ≥1.5 mg/dl and active treatment for diabetes mellitus). Since then there have been many studies of the choice of contrast agent as a risk factor for CIN.[15,18,19] Those studies have generally tested the hypothesis that an iso-osmolality contrast media (IOCM) agent such as iodixanol would further reduce the risk of CIN compared to LOCM, just as LOCM had reduced the risk compared to HOCM. As the risk of CIN is much lower with LOCM than with HOCM, it was imperative that these trials included adequate numbers of high-risk patients to demonstrate superiority of IOCM. However, many studies simply had too few patients at high risk for CIN to allow meaningful interpretation. The main problem with most of these studies was the use of eGFR of <60 ml/min as a key inclusion parameter. As noted above, this criterion would likely reduce the power of any study to detect a difference in outcome.
On the other hand, a number of studies have shown a benefit of IOCM in terms of outcomes and risk of CIN. The Nephric trial, a multicenter, European, prospective, randomized trial, showed that iodixanol use resulted in significantly less CIN than the LOCM comparator iohexol when both were administered intra-arterially to high-risk patients with CKD and diabetes mellitus. Other trials supported this finding, including two performed in Asia[20,21] and a recent large meta-analysis.
Several studies have suggested that the particular LOCM used may have played a role in the outcome of the trials. This hypothesis was based on the fact that in the trials which failed to show a benefit of IOCM compared to LOCM, iopamidol (rather than iohexol) was the comparator LOCM.[15,19] Unfortunately, this hypothesis has not been directly tested. In a recent trial using a similar patient population and study protocol to the Nephric trial (and conducted by several Nephric investigators), iopamidol and iodixanol use resulted in similar rates of CIN. However, key differences were noted between the two trials. For example, approximately 30% less contrast medium volume and 50% more volume expansion prior to administration were used in the iopamidol trial compared to Nephric.[15,18]
As to why iopamidol would have a lower risk of CIN than iohexol, a clear mechanistic explanation is lacking. Each agent has a similar osmolality and each is a monomeric iodinated benzoic acid derivative, although they differ in chemical composition by minor side chain configurations.[23,24] Until direct comparisons between iopamidol and iohexol are carried out in high-risk populations, there is little basis for concluding that one agent is safer than the other. Moreover, a recent analysis of the Premier Patient Database, a repository of more than 200,000 patients, failed to find a difference in the risk of CIN between patients receiving iohexol and those receiving iopamidol.
It would appear, then, that IOCM may convey protection against CIN in high-risk patients, particularly those receiving larger volumes of contrast medium or those less able to tolerate larger intravenous saline loads prior to radiologic studies. Radiologists should therefore consider this possibility when selecting a contrast agent.
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