Dr Brendan Barrett is a Professor of Medicine in nephrology and clinical epidemiology at Memorial University of Newfoundland. His current research is focused on clinical care for patients with chronic kidney disease. He has published studies related to the general and kidney-related adverse effects of contrast media.

Dr BJ Barrett
Division of Nephrology and Clinical Epidemiology Unit Memorial University of Newfoundland St. John's, Newfoundland, Canada

Key words: contrast media; nephrotoxicity; contrast-induced nephropathy

Address for correspondence:
Dr BJ Barrett
Division of Nephrology, Health Sciences Center
St. John's, Newfoundland, Canada, A1B 3V6
Tel: +1-(709)-777-8073
Fax: +1-(709)-777-6995
E-mail: bbarrett@mun.ca

Abstract
Contrast-induced nephropathy (CIN), an acute decline in renal function after administration of an iodinated contrast medium, remains an important problem that can prolong hospitalisation, and increase morbidity and mortality. The pathogenesis probably involves a combination of ischaemic and direct tubulotoxic effects. Impairment of renal function is normally mild and transient, but in some patients, such as those with pre-existing renal impairment (especially when coupled with diabetes mellitus), clinically significant renal impairment can develop and dialysis may be required. The exact incidence of clinically significant CIN is not clear, partly owing to variations in definition and co-morbidity in study populations. The risk of renal failure averages about 3% in prospective studies of patients without risk factors; dialysis is required in <1% of patients after percutaneous coronary intervention. Risk factors should be corrected where possible and patients in whom they cannot should receive the smallest possible dose of contrast medium. Management of severe CIN is no different from that for acute renal failure of any aetiology. No beneficial pharmacological treatment for established CIN has been identified. Renal function normally recovers after CIN. However, up to 30% of patients have some degree of permanent renal impairment but this may not be due solely to CIN.

Introduction
Iatrogenic acute renal failure remains a significant problem, substantially increasing morbidity and mortality in those affected. The nephrotoxicity of iodinated radiocontrast media was implicated as the third most common cause of acute renal failure in hospitalised patients in the early 1980s and again in the late 1990s.^1,2 The increasing availability, use and variety of procedures requiring radiographic contrast media, combined with increasing age and co-morbidity of the treated population, contribute to the continuing importance of contrast-induced nephropathy (CIN).

Contrast-induced nephropathy is commonly defined as an acute decline in renal function following the administration of intravascular iodinated contrast media, in the absence of other causes. For research purposes, definitions such as a proportionate (e.g. 25% or 50%) or absolute (e.g. 0.5 mg/dL, 50 ΅mol/L) rise in serum creatinine above the baseline value are commonly used. Awareness of the nephrotoxicity of contrast media and the factors predisposing patients to CIN has improved over time, but a recent survey of referring clinicians in university medical centres suggested that the risk associated with some specific medical conditions was overestimated.³ Much of the recent research in this area has been directed at means of minimising risk, or preventing CIN, and this will be discussed in another contribution to this journal. This article reviews the pathogenesis, clinical features, diagnosis, and management of CIN.

Pathogenesis
In animals, at least, the pathological findings associated with CIN include vacuolisation of proximal tubular cells and congestion of the sub-cortical medulla.⁴ The pathogenesis is not entirely understood, but probably involves a combination of ischaemic and direct tubulotoxic effects together with tubular obstruction. The pathogenesis has been difficult to study as significant injury due to contrast alone is rarely seen. Existing animal models involve other factors impairing renal function in addition to contrast, thus mimicking the situation in the patients at risk clinically. The mechanism of injury may vary by contrast type, partly as a result of differences in tubular secretion and pinocytosis of contrast.⁵ The injection of contrast induces a biphasic haemodynamic change in the kidney, with an initial transient increase followed by a more prolonged decrease in global renal blood flow.⁶ In the period of lower flow, there is cortical vasoconstriction and outer medullary vasodilation and congestion.⁴ The cortical vasoconstriction may be due to compression of vessels resulting from increased hydrostatic pressure in tubules and interstitium and alteration in vasoactive substances including endothelin, vasopressin, prostacyclin, nitric oxide and adenosine.^6–10 Tubulo-glomerular feedback seems to contribute, at least with high-osmolality media.¹¹ Despite increased medullary blood flow, medullary hypoxia occurs, which may lead to injury due to an imbalance of oxygen demand and supply.⁹ Demand is increased by the osmotic diuresis induced by contrast excretion.9 This is reflected clinically in the lower incidence of CIN associated with contrast media of low- or isosmolar type.12–15 In addition, factors that impair medullary vasodilation, such as non-steroidal anti-inflammatory drugs (NSAIDs), tend to worsen CIN. Some attempts to prevent CIN in clinical settings by interventions affecting renal blood flow have not worked. However, broadly active drugs that do not specifically moderate the impact of contrast on regional oxygen supply and demand might not be expected to have benefit. Studies are now starting to aim at more specific targets, such as the dopamine-1 receptor, with more subtle impact on intra-renal haemodynamics.¹⁶

Although it has been suggested,¹⁷ there are no good data demonstrating that tubular obstruction by contrast-induced increases in Tamm-Horsfall proteins,18 uric acid or oxalate crystals plays a major role in CIN. A potential role for direct tubular cell toxicity is suggested by in vitro studies.^19,20 Oxidant-mediated injury may also be involved.^21,22

Clinical features and diagnosis
Patients with CIN are generally asymptomatic and present only with an acute rise in serum creatinine 24 to 72 hours after the administration of intravascular contrast. The renal failure is usually non-oliguric, but may be oliguric, especially if there is significant renal impairment prior to contrast.^23,24 Serum creatinine typically peaks at 3 to 5 days and returns to baseline 7 to 10 days after the procedure.⁶ A serum creatinine rise of =0.5mg/dL within 24 hours of contrast is predictive of the absence of clinically significant further acute renal failure.²⁵ In a minority of cases renal function does not recover to pre-contrast values or the renal failure is severe enough to require dialysis. Baseline renal impairment – especially with diabetes mellitus – cardiac failure, dehydration and high doses of contrast all increase the chance that clinically significant renal impairment will occur.^12,26

To make an unequivocal diagnosis of CIN, other potential causes of acute renal failure must be ruled out. For patients exposed to contrast, pre-renal factors, atheroembolic disease and other nephrotoxic insults are high on the list of differential diagnoses. However, as with acute renal failure in general, contrast nephrotoxicity may be only one of several predisposing or precipitating factors leading to a decline in renal function around the time of a contrast-requiring procedure. The relatively rapid onset and typical course of events may help differentiate CIN from other aetiologies, but the exact contribution of contrast can be hard to discern in multifactorial cases.With CIN, urinalysis may demonstrate granular casts, tubular epithelial cells and proteinuria, but may be unremarkable. Most, but not all, patients exhibit low fractional excretion of sodium.^6,23

Epidemiology
Very mild, transient changes in renal function occur in almost all patients who receive intravascular radiocontrast.²⁷The exact incidence of clinically significant CIN is not clear, however, as prospective studies have produced a wide range of estimates. The inconsistencies are at least partly explained by differences in the sensitivity of criteria used to define the condition. Study populations have also varied in the level of co-morbidity and hence the presence of other potential causes of acute renal failure. One large observational study reported a rate of 14.5% in a series of 1800 patients undergoing cardiac angiography.²⁸ In the absence of risk factors, the risk of renal failure averages about 3% in prospective studies.²⁹ The risk of CIN rises dramatically with the number of risk factors present. In one study, the incidence rose progressively from 1.2% to 100% as the number of risk factors went from zero to four.³⁰ Recently reported, prospectively collected registry data suggest that the general incidence of nephropathy requiring dialysis after percutaneous coronary intervention is 0.44%.²⁶ It is unclear whether the route of administration (intrarenal arterial injection, other arterial or intravenous) is important in determining toxicity: a study that randomised the route was confounded by dose difference and limited by small numbers.³¹

Management and outcome
In most instances, CIN never becomes clinically evident and renal function returns to baseline within a week or so. In more severe cases, the management is no different than that for acute renal failure of any other aetiology. Careful control of fluid and electrolyte balance, avoidance of further nephrotoxic insults, attention to nutrition and surveillance for complications is generally all that is required, although dialysis may occasionally be necessary.^13,26,32 The hypothesised ischaemic nature of injury has prompted some studies of vasodilating agents for the treatment of established CIN, but the results have been disappointing. A randomised trial of atrial natriuretic peptide did not demonstrate an overall reduction in the requirement for dialysis in a subgroup of patients with CIN.³³ Another trial compared dopamine to saline infusion in 72 patients who developed nephropathy after coronary angioplasty: patients in the dopamine group had higher peak serum creatinine and required dialysis more frequently than controls.³⁴ A randomised trial of prophylactic haemodialysis soon after contrast in patients with pre-contrast serum creatinine >200 ΅mol/L failed to demonstrate any benefit in renal protection or avoidance of adverse clinical events.³⁵ Dialysis does not need to be done either for prevention of CIN in those at risk, or for routine removal of contrast after imaging in previously dialysisdependent cases.³⁶

The outcome of CIN is usually recovery of renal function. As many as 30% of patients have some degree of permanent renal impairment, but this may be partly due to other illnesses present or medications used at the time CIN developed.³⁷ Acute renal failure of any aetiology, including CIN, can prolong hospital stay.³⁴ Contrast-induced nephropathy may be associated with an increase in mortality as well.^38,39 Mortality in patients with CIN was 34% compared with 7% in controls matched for age, baseline serum creatinine, diagnostic procedure and APACHE II (acute physiology and chronic health evaluation) score (P<0.001).³⁸ Another retrospective analysis of a consecutive series of patients with pre-existing renal impairment undergoing coronary intervention found similar results, with in-hospital mortality of 14.5% among those who developed CIN, versus 4.9% among those who did not.³⁹ Furthermore, at one year, mortality was 45.2% for those with nephropathy requiring dialysis, 35.4% for those with less severe nephropathy, and 19.4% for those who did not develop nephropathy. Multivariate modelling revealed that age, nephropathy and some characteristics of the coronary lesions were the only independent predictors of mortality.

Conclusions
Contrast-induced nephropathy remains an important problem with significant consequences. The pathogenesis seems to relate to ischaemic and possibly direct tubulotoxic injury, especially in the outer medulla. The condition is not common in the absence of other risk factors and these – chronic renal impairment, especially with diabetes, and dehydration – are generally detectable with a history and physical examination. Risk factors should be corrected whenever possible; when they cannot, patients should receive the smallest dose of contrast feasible and have their serum creatinine measured after the procedure. Supportive care is indicated in cases of CIN.

What we knew before and what this tells us ● Contrast-induced nephropathy (CIN) is an important cause of acute renal failure,     particularly in at-risk patients ● The pathogenesis is thought to involve ischaemic and tubulotoxic effects and     vasoactive mediators ● Low osmolar and isosmolar contrast media are associated with a lower risk of CIN     than high osmolar contrast media, probably as a result of the lesser osmotic diuresis     they induce and the resultant lower oxygen demand ● Renal impairment is usually mild and non-oliguric ● Management of more severe renal impairment is the same as that for acute renal     failure of any other aetiology ● No effective pharmacological treatment for established CIN has been identified ● Mortality is higher in patients who develop CIN than in those who do not ● Amongst patients who develop CIN, mortality is higher in those requiring dialysis

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