In 1942, Pendergrass et al.1 reported renal function impairment associated with the use of radiographic contrast media for the first time. Those authors studied 16 patients who died after undergoing excretory urography. Nine of the 16 patients had acute renal failure (ARF). In 1954, oliguric ARF directly associated with the use of contrast media was reported for the first time in a patient with multiple myeloma who underwent intravenous pylography.2 Since then, contrast-medium induced nephropathy (CIN) has been the focus of studies aiming to clarify its pathophysiology and to develop preventive strategies. With the rapid development of interventional cardiology in the last decades, coronary cineangiography and coronary angioplasty have gradually become part of the diagnostic and therapeutic strategy for patients with ischemic heart disease. CIN, as a potential complication of these procedures, has acquired a progressively greater clinical relevance. Its incidence is relatively high and varies according to the definition used, being more frequent in determined subgroups of patients. In fact, CIN is one of the most common causes of acquired ARF in the hospital environment. It significantly increases in-hospital morbidity and mortality, prolongs hospital stay, and results in increased costs.3,4 Solomon et al.5 reported that even a small increase in serum creatinine (Cr) following contrast medium use is related to a mean 4-day increase in hospital stay. Definition. No widely accepted definition of CIN exists. In one of the first initiatives, Berkeseth and Kjellstrand6 defined CIN as a sudden deterioration in renal function after administration of radiographic contrast media, excluding all other possible etiologies. A more functional definition, however, is required. Currently, CIN is most commonly defined in clinical trials as a 25% increase in baseline serum creatinine or an absolute increase of 0.5 mg/dl in serum creatinine measured between 48 and 72 hours after exposure to the contrast media. An absolute increase in baseline serum creatinine appears to be the most useful and practical definition. Physiopathogenesis. The physiopathogenesis of contrast-medium induced acute renal failure has not yet been completely understood. Two hypotheses have been formulated about the major mechanisms involved: 1) ischemia of the renal medulla and 2) direct injury of the renal tubular cells. The renal medulla is extremely susceptible to hemodynamic alterations, which, although subtle, are sufficient to compromise the equilibrium between high metabolic need and tissue oxygen delivery.7 The renal vascular bed reacts to injections of hyperosmolar solutions with initial vasodilation followed by prolonged vasoconstriction.8 A study reported that renal hypoperfusion occurs after contrast medium infusion and is proportional to the osmolality of the contrast medium.9 This may cause ischemia in the renal medulla and suppression of renal function after the administration of hyperosmolar contrast media. The hypothesis of direct tubular injury caused by contrast medium was raised more than 2 decades ago,10 but it has been studied in more detail only in recent years. After contrast medium infusion, an increase in the renal production of free radicals is evident.11 In animals, contrast medium infusion increases lipid peroxidation,12 which is a marker of oxidative stress, suggesting that direct tubular injury caused by contrast medium plays a fundamental role in the genesis of CIN. In addition, some substances, such as adenosine, calcium and endothelin, may be related to the physiopathogenesis of CIN, either by acting on the regulation of renal flow or by playing an important role in the release of free radicals.11,13–16 Incidence and risk factors. The incidence of CIN has ranged from 1% in previously healthy patients to more than 50% in high-risk groups.17–19 This difference may be attributed not only to the population studied, but also to the definition of CIN adopted. The 2 major risk factors for the development of CIN are a previous decrease in renal function20–22 and diabetes mellitus (DM).23 Approximately 5% of the general population has an increase of at least 0.1 mg/dl in serum creatinine after coronary angiography.24 A study of 1,826 consecutive patients undergoing coronary intervention reported a 14.5% incidence of CIN when a 25% increase in serum creatinine was considered.23 Gruberg et al.25 studied a consecutive series of 439 patients undergoing coronary intervention with baseline creatinine above 1.7 mg/dl. Deterioration of renal function (increase of 25% in serum creatinine) was observed in 37% of the patients, of whom 7% required hemodialysis. In the largest case series26 published so far comprising 7,586 consecutive patients undergoing coronary intervention, the incidence of ARF, defined as an absolute increase in creatinine of at least 0.5 mg/dl 48 hours after the procedure, was 3.3%. In that series, the independent risk factors for the development of CIN were as follows: previous suppression of renal function, age, history of myocardial infarction in the previous 24 hours, heart failure, DM and the presence of peripheral vascular disease. Diabetes mellitus was associated with CIN for the first time in 1973 by Barshay et al.27 Later on, several other studies confirmed that DM is an important risk factor for CIN.28–31 This relation is independent of the presence of clinically detectable diabetic nephropathy,24 and the risk is high even in patients with normal levels of serum creatinine.26 However, the risk is cumulative, and diabetic patients with nephropathy have a greater risk of developing this complication. In diabetic patients with creatinine levels between 2.0 mg/dl and 4.0 mg/dl, the incidence of CIN is approximately 30%, and in those with creatinine levels above 4.0 mg/dL, the incidence of CIN may reach 80%.32 In another study assessing diabetic patients with azotemia and undergoing coronary angiography, 50% of the patients had a 25% increase in creatinine and 12% of them required hemodialysis.33 Previous suppression of renal function is an independent risk factor for CIN at least as important as DM. Patients with creatinine levels greater than 1.5 mg/dl are identified as being under a higher risk.34 The chance of developing CIN may be up to 7 times greater in patients with chronic renal failure.26,35 In a large series, previous suppression of renal function was the factor most strongly associated with the development of contrast-medium induced ARF.26 Table 1 shows the independent risk factors for CIN reported in major studies with multivariate analysis. Other risk factors frequently described as associated with CIN are as follows: presence of multiple myeloma, volume depletion, use of certain medications (gentamycin, nonsteroidal anti-inflammatory agents)36 and left ventricular dysfunction.23 Laboratory diagnosis. Creatinine is the major clinical marker used to diagnose CIN, the most important manifestation of which is a progressive increase in serum creatinine levels, beginning 24 hours after exposure to the contrast medium.37 Creatinine levels reach a peak in 48–72 hours, returning to baseline levels in approximately 7 days.36 Some studies evaluated the alterations in urinary parameters as early diagnostic evidence for CIN.38,39 The alterations in sodium excretion fraction, transient proteinuria and enzymuria were not useful for confirming the diagnosis of CIN.37,40 Recently, serum levels of angiotensin-converting enzyme, urinary albumin, and urinary excretion of gamma glutamyl transferase and N-acetyl-b-D-glucosidase (NAG) have been regarded as sensitive markers for the diagnosis of subclinical CIN.41 However, the evidence is not yet sufficient to support their use in clinical practice. Clinical manifestations. Most patients with CIN have high serum creatinine levels with no clinical repercussions; some patients may have oliguria, which is transient most of the time. CIN, however, increases hospital stay, morbidity and mortality. Rihal et al.,26 in a study of 7,586 consecutive patients undergoing coronary intervention, reported an in-hospital mortality rate of 22% in the group with CIN (an absolute increase in creatinine >= 0.5 mg/dl 48 hours after the procedure) and 1.4% in the group without CIN. Levy et al.,4 in a case control study of 183 patients with mean baseline creatinine of 1.6 mg/dl who had undergone procedures with radiographic contrast media and developed CIN (an increase in creatinine >= 25% as compared with the baseline level in 48 hours), reported a mortality rate of 34% in the group of patients as compared to 7% in the control population. McCullough et al.23 reported a 7.1% mortality rate in patients with contrast-medium induced ARF versus a 1.1% mortality rate in the group without ARF in a series of consecutive patients undergoing percutaneous transluminal coronary angioplasty (PTCA). In addition, patients with CIN had a hospital stay 3 times longer than those who did not develop CIN, and the intensive care unit stay is also significantly increased.42 Only a small number of patients developing CIN require hemodialysis; approximately 1.4% of all patients with renal function suppression following contrast medium administration require that type of treatment.43 However, in subgroups of high-risk patients, this rate may reach 12%.4 For patients requiring hemodialysis, mortality is even greater and may reach 62%.4 In addition to greater in-hospital mortality, patients with CIN have a poorer prognosis in the medium and long run. In patients at high risk for developing CIN, the 1-year mortality rate was 38% in the group with CIN and 20% in the patients whose creatinine levels did not increase.25 Similar data were found by Rihal et al.,26 who reported 6-month and 1-year mortality rates of 12% and 45%, respectively, in patients with CIN versus 3.7% and 14.5%, respectively, in patients without CIN. Among patients requiring hemodialysis, the in-hospital mortality rate ranged from 25–35.7%,23,44 and even reached 55% by the end of 1 year.44 Prevention. Because no specific and effective treatment for CIN exists, studies have been directed to the search for efficient and preventive measures. The preventive measures most studied so far are discussed in the following sections and are summarized in Table 2. 1) Hydration. Because dehydration is a well-known risk factor for renal function suppression following exposure to radiographic contrast media, hydration with sodium chloride solution has been uniformly accepted as a prophylactic measure for CIN prevention, although no clinical trials comparing hydration and absence of hydration have been published. In patients at higher risk for developing CIN, intravenous hydration with 0.45% sodium chloride alone (from 12 hours prior to the procedure to 12 hours after the procedure) is better than hydration associated with diuresis induced with either furosemide or mannitol.5 Recently, Mueller et al.,45 in a randomized study comprising 1,620 consecutive patients undergoing PTCA, compared the administration of an isotonic physiologic saline solution (0.9% sodium chloride) with a hypotonic solution (0.45% sodium chloride + 5% glucose). The incidence of CIN was significantly lower with the isotonic solution (0.7% versus 2.0%). However, the regimen of intravenous hydration for a period of 24 hours makes ambulatory procedures difficult. A small study involving patients referred for elective cardiac catheterization suggested that an oral hydration regimen at home associated with intravenous hyperhydration at the beginning of the procedure produces results similar to those of intravenous hydration with 0.45% sodium chloride extending from 12 hours prior to the procedure to 12 hours after the procedure.46 This strategy of ambulatory hydration could be an alternative to elective procedures in patients with renal function suppression. 2) Contrast medium type. Conventional radiographic contrast media use iodine to absorb x-ray photons and to generate a visible radiographic image. These agents are frequently hyperosmolar and ionic. These characteristics contribute both to nephrotoxicity and to allergic reactions. Both ionic and nonionic radiographic contrast media with lower osmolality have been developed. Experimental studies47,48 reported that low osmolality contrast media have a lower nephrotoxic potential. Some clinical studies did not report a reduction in the incidence of CIN with low osmolality contrast media, either ionic or nonionic.49,50 Most of the studies, however, reported that the use of low osmolality contrast media is effective in preventing CIN in patients with previous renal function suppression and in diabetic patients.51,52 A meta-analysis comprising 31 studies involving both cardiac and non-cardiac procedures showed that patients with previous renal function suppression benefit from the use of low osmolality contrast media.53 Recently, Aspelin et al.,54 in a study involving 129 patients with serum creatinine above 1.5 mg/dl who underwent cardiac and aortofemural angiography, showed that the use of the iso-osmolar nonionic contrast media, iodixanol, resulted in a significantly lower incidence of CIN when compared with iohexol, a low osmolality nonionic contrast media. The primary endpoint was the peak increase in the serum creatinine within 3 days of the procedure. The peak of serum creatinine was 0.13mg/dl in the iodixanol group as compared with 0.55 mg/dl in the iohexol group. 3) Contrast volume. It is agreed that the smaller the volume of contrast media administered, the lower the risk of CIN. In patients receiving less than 100 ml of contrast medium, the risk of CIN is very low.23 Cigarroa et al.55 proposed a formula based on the patient’s weight and serum creatinine (5ml of contrast x kg body weight/serum creatinine) to calculate the safety limit of a contrast medium to be administered to patients with chronic renal failure under conservative treatment. In that study, patients exceeding the safety limit calculated for the contrast medium administered during the procedure had a significant increase in the incidence of CIN. 4) Prostaglandin. Prostaglandin E1 (PGE1) has a vasodilating effect because it inhibits the transcription of endothelin,56 which increases blood flow in renal medulla. It has also been reported to have a renal cytoprotective effect.57 In a double-blind randomized study, Koch et al.58 assessed the prophylactic use of PGE1 in 117 patients with previous renal function suppression who had undergone several diagnostic procedures with contrast medium administration. The PGE1 dosages tested were 10, 20 and 40 ng/kg/minute intravenously for 6 hours, starting 1 hour prior to the procedure. The effect of 20 ng/kg/minute of PGE1 in preventing CIN was superior to placebo and that of the administration of the other dosages of PGE1. However, that study comprised a small number of patients and only suggested that this drug might be beneficial. Larger studies are required to confirm that hypothesis. 5) Calcium channel antagonists. Experimental studies have suggested that calcium channel antagonists might be beneficial for preventing CIN by improving renal ischemic and toxic injury.9 However, few clinical trials about this issue have been published, and all of them comprised a reduced number of patients and reported contradictory results. In a placebo-controlled randomized study59 with 85 consecutive patients undergoing imaging examinations with radiographic contrast media, the prophylactic use of nifedipine showed no benefit in preventing CIN. Another double-blind randomized clinical trial assessed the prophylactic use of nitrendipine in 35 patients undergoing radiographic examinations.60 In the group randomized to the active treatment, no alteration in renal function was observed; however, in the placebo group, a significant 27% reduction in the glomerular filtration rate was found. 6) Fenoldopam. This drug is a potent vasodilator that acts as a selective agonist of the dopaminergic D1 receptors, and is used in the treatment of hypertensive crisis. In the kidney, unlike other vasodilators, it increases both the cortical and medullary blood flows. Two clinical trials61,62 analyzed the use of fenoldopam in the prophylaxis of CIN in patients with previous renal function suppression. In a retrospective study,61 forty-six patients treated with fenoldopam were compared to historic controls with similar risk factors. The incidence of CIN was 13% in the fenoldopam group and 38% in the control group. In a prospective study,62 a total of 150 patients whose creatinine levels were greater than 1.5 mg/dl underwent PTCA and received fenoldopam. Only 4.7% of the patients treated developed CIN, as compared to 18.8% of the historic controls. Those studies, however, were small and were compared with historic controls; therefore, they cannot be accepted as definitive evidence. Further clinical trials are required to confirm the benefit of that drug. 7) Hemodialysis. Lehnert et al.,63 in a randomized study, assessed the prophylactic use of hemodialysis for 3 hours in patients with serum creatinine above 1.4 mg/dl who underwent both cardiac and non-cardiac procedures, beginning immediately after the radiographic examination, in an attempt to eliminate the contrast medium and minimize its deleterious effects on the kidneys. The results indicated that this strategy was not useful for preventing CIN. Continuous hemofiltration (10 hours before and 10 hours after the procedure) was also assessed in the prophylaxis of CIN in 54 high-risk patients (Cr > 2.0 mg/dl) undergoing PTCA.64 The results were extremely favorable to hemofiltration in regard to in-hospital mortality (2.4% versus 14.7%) and the need for hemodialysis (0% versus 39%). However, it is worth noting the invasive and extremely expensive nature of that procedure. 8) Theophylline. Theophylline, a nonselective antagonist of the adenosine receptors, was assessed for preventing CIN. The results, however, were inconclusive. In a placebo-controlled randomized study65 comprising 100 patients with previous renal function suppression, the incidence of CIN was significantly reduced from 16% in the group receiving placebo to 4% in the group receiving theophylline in 48 hours. In another prospective randomized study66 comprising 60 patients with the same characteristics, aminophylline + hydration was compared with hydration alone and dopamine + hydration. No significant difference was observed in the incidence of CIN in the 3 groups studied (35% versus 30% versus 50%, respectively). Erley et al.67 also assessed the use of theophylline in a double-blind randomized study comparing hydration in 80 patients with chronic renal failure. The use of theophylline showed no additional benefit to hydration. 9) Angiotensin-converting enzyme inhibitors (ACE inhibitors). The possible role of medullary ischemia mediated by the renin-angiotensin system raised the hypothesis that ACE inhibitors could be useful for preventing CIN. The prophylactic use of captopril was assessed in diabetic patients undergoing coronary angiography.68 The results showed that the drug was useful for preventing CIN in diabetic patients with a significant risk reduction of 79%. In that randomized study, however, only 71 patients were included. Therefore, larger clinical trials are required to confirm the beneficial effects of the ACE inhibitors in this subgroup of patients. 10) Dopamine. Low doses of dopamine have a renal vasodilating effect, causing an increase in the glomerular filtration rate and renal blood flow. Two randomized studies assessed the use of low doses of dopamine for preventing CIN. One of these studies66 compared the use of dopamine combined with hydration, aminophylline combined with hydration, and hydration alone in patients undergoing PTCA. Another study69 with dopamine comprised 66 patients who underwent coronary angiography and were randomized to receive dopamine at the dosage of 2 µg/kg/minute combined with 0.45% saline solution or 0.45% saline solution alone. The results of both studies did not confirm the potential benefit of dopamine in preventing CIN. In addition, in patients with peripheral vascular disease, the use of dopamine may significantly worsen renal function as compared with the use of placebo.69 11) Atrial natriuretic peptide. The atrial natriuretic peptide is an inhibitor of the synthesis of vasopressin, which is a potent vasoconstrictor. Therefore, by improving renal blood flow, the atrial natriuretic peptide could reduce the incidence of CIN. That drug was assessed in the prophylaxis of CIN in a prospective study comprising 247 patients at risk70 who were randomized to receive placebo or atrial natriuretic peptide at 3 different dosages. The results showed that none of the atrial natriuretic peptide dosages assessed were able to reduce the incidence of CIN as compared to placebo. 12) N-acetylcysteine. There is evidence that the production of free radicals in the kidney increases after the administration of contrast media.12 N-acetylcysteine, an antioxidant, also has vasodilating properties because it increases the expression of the nitric oxide synthetase enzyme71 and can prevent contrast-medium induced renal failure both by reducing direct oxidative injury and by improving renal hemodynamic conditions. Tepel et al.72 reported that in patients with previous renal function suppression undergoing contrast-enhanced computed tomography, the administration of N-acetylcysteine at a dosage of 600 mg twice daily for 2 days significantly reduced the incidence of renal dysfunction caused by contrast medium from 21% in the group receiving placebo to 2% in the group receiving the drug. This result was confirmed in another small clinical trial assessing the use of N-acetylcysteine in 54 patients at risk who were undergoing cardiac catheterization.73 Recently, in a placebo-controlled randomized study74 comprising 183 patients with previous renal function suppression undergoing coronary angiography, coronary angioplasty or peripheral angiography, N-acetylcysteine was not useful for preventing CIN in the population studied. A post hoc analysis showed that the drug had a beneficial effect only in the subgroup of patients receiving a small volume of contrast medium (Conclusion. Contrast-medium induced nephropathy in patients undergoing cardiac catheterization has an extremely variable incidence, which is very elevated in high-risk subgroups. Despite its benign course in most cases, it is associated with a longer hospital stay, and elevated in-hospital and late mortality rates. Therefore, preventive measures are important. Up to the present time, hydration with an isotonic solution extending from 12 hours before the procedure to 12 hours after the procedure has been the most effective measure. In patients at high risk for developing CIN, such as diabetic patients and those with chronic renal failure, the use of low osmolality agents should be considered, because these agents were beneficial in most clinical trials. N-acetylcysteine is a safe and inexpensive alternative, which proved to be useful for preventing CIN in early studies. However, larger clinical trials with N-acetylcysteine are still required to definitively confirm its efficacy in preventing CIN.
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