Department of Nephrology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
Correspondence and offprint requests to: Gilbert Deray, Department of Nephrology, Group Hospitalier PitieSalpêtriere, 83 Boulevard de l'Hôpital, F-75651 Paris Cedex 13, France.
Intravascular iodinated contrast media administration continues to be a common cause of hospital acquired acute renal failure [1]. In the past decade our understanding of the pathogenesis of this association has led to improvement in our ability to prevent and manage this complication. In this review we have detailed the progress which has been made in this field in our department under the direction of Claude Jacobs.
Incidence of nephropathy
The reported incidence of radiocontrast-induced nephropathy (RCN) varies from 0 to 100% in retrospective studies [2,3]. This results from the lack of a single reliable definition, the method of investigation and differing patient population. Large prospective controlled studies have been reported by several authors. In non-diabetic patients with normal renal function or moderate renal insufficiency, Parfrey et al. [4] reported an incidence of RCN at 2.12.4% but no significant difference was found between these patients and the control group. In patients with chronic renal insufficiency, the incidence was 7% compared with 1.5% in the control group. The risk of acute renal failure attributable to the contrast agent was therefore 5.5% and the relative risk associated with the infusion of contrast material was 4.5%. Manske et al. [5] assessed the incidence of RCN in 59 insulin-dependent diabetic patients with severe chronic renal failure who underwent coronary angiography. The control group included 21 azotaemic patients with insulin-dependent diabetes undergoing evaluation for renal transplantation. Serum creatinine levels 24 h after radiocontrast exposure were increased more than 10% above baseline in 25 of 59 patients and one control subject.
Clinical presentation
The clinical presentation of RCN involves the asymptomatic increase of serum creatinine concentration occurring within 2472 h of a contrast study with or without associated oliguria. Other clinical parameters, including examination of urine sediment, urine electrolyte determinations, and detection of a persistent nephrogram on a plain abdominal film, are neither sensitive nor specific and contribute little to the diagnosis of RCN. Once RCN is established, renal function remains depressed for 13 weeks in most cases and then returns to baseline or near-baseline levels.
Spontaneous recovery is to be expected, with less than 10% of patients requiring dialytic intervention. Attempts to reverse RCN largely have been unsuccessful and supportive care generally is required. Occasionally, renal failure is irreversible and thus requires long-term dialysis.
Risk factors
The list of risk factors purported to predispose to radio-contrast-induced acute renal failure is long and includes renal insufficiency, diabetes mellitus, multiple myeloma, volume depletion, dehydration, concomitant exposure to other nephrotoxins, repeated exposure to radiocontrast over a few days, volume of contrast, injection side (i.e. intra-arterial versus intravenous), hypotension and renal ischaemia [6,7]. Other possible clinical risk factors postulated but not confirmed include hyperuricaemia, hypertension, age, anaemia, proteinuria and renal transplantation. The most frequently cited independent risk factor is pre-existing renal insufficiency. Diabetes without concurrent overt nephropathy does not appear to be a significant risk factor.
The use of intravenous contrast media (CM) administered in multiple myeloma patients has been equated with acute renal failure. In accordance with this finding, many physicians believe that intravenous CM is contraindicated in myeloma patients. In a meta-analysis of seven retrospective studies of myeloma patients receiving CM, the prevalence of RCN was noted to be only 0.61.25%. Therefore, although not totally risk-free, the administration of CM may be performed under very careful medical supervision and with hydration of patients.
Mechanisms
A variety of mechanisms have been suggested to play roles in the pathophysiology of radiocontrast-agent-induced acute renal failure. They include direct toxicity [8], haemodynamic alterations [9] and tubular obstruction. The biphasic response in total renal blood flow to infusion of CM is well known [9]. It consists of an initial brief rise in renal blood flow followed by a prolonged fall with a gradual return to baseline. The mechanism (or mechanisms) that mediates the reduction in renal blood flow and glomerular filtration rate remains unclear. Efforts to abolish effectively the vasoconstrictor response with alpha-adrenoceptor antagonists, angiotensin II blockers and angiotensin-converting enzyme inhibitors have proven unsuccessful.
Animal experiments in healthy animals have shown that intravenous or intra-arterial infusion of contrast medium in a clinically acceptable dose produces only minor transient alterations in total renal blood flow not sufficient to produce persistent renal dysfunction.
However, renal impairment occurs more frequently in patients with pre-existing renal disease, diabetes mellitus, atherosclerosis, severe renal artery stenosis or cardiac failure. All these situations have in common alterations in renal haemodynamics leading to ischaemic lesions of variable magnitude. Furthermore erythrocyte deformability is reduced in the presence of high osmolar contrast media (HOCM), augmenting blood viscosity and leading to further regional hypoperfusion, especially in the already hyperosmolar milieu of the medulla. Further, a leftward shift of the O2 haemoglobin dissociation curve takes place in vitro when contrast material is added to whole blood, leading to a decrease in O2 availability to tissues. Finally, selective medullary hypoperfusion was found by comparing cortical and papillary blood flow following the administration of various contrast agents [10,11]. Because tissue partial pressure of O2 is remarkably low within the renal medulla compared with the cortex, and because the medullary thick ascending limb (mTAL) is characterized by a high metabolic rate due to an active ion pump mechanism, medullary hypoxia could play a central role in the susceptibility of the kidney to contrast material. It has been shown that rats exposed to various combinations of renal insults developed acute renal failure after CM administration. Morphologic studies showed selective hypoxic damage to mTALs in the outer medulla. No other structural damage was noted elsewhere in the kidney. A correlation between the severity of mTAL damage and the degree of renal failure was found. Comparable findings were described in a rabbit model by others. Furthermore, severe and protracted outer medullary hypoxia follows the intravenous injection of contrast media. In this model, contrast media injection also was associated with an incomplete removal of erythrocytes from the outer medullary blood vessels and a strong correlation between erythrocyte mass in the interbundle zone and mTAL necrosis was evidenced [12].
A deleterious effect of CM injection on medullary blood flow is supported further by a recent study showing that radiocontrast-induced pathologic and functional damage in rats may be modulated by manipulating the nitric oxide system, which appears to participate in the regulation of medullary blood flow and oxygen balance. These findings strengthen the role of hypoxia as a cause of radiocontrast-induced tubular damage.
It has already been shown that dehydration potentiates the vasoconstrictive effects of contrast media [13]. We postulated that in the setting of severe renal ischaemia the renal haemodynamic effects of CM might be enhanced. To verify this hypothesis we have assessed the renal vasoconstriction induced by CM before and after inducing renal ischaemia in the dog.
Diatrizoate (HOCM), iopamidol and ioxaglate (both low osmolar contrast media, LOCM) were injected within 15 s at 20 min intervals, at the dose of 1 ml/kg during a control period and 15 min after applying an aortic clamp to reduce the renal perfusion pressure to 70 mmHg [13]. During the control period iopamidal, ioxaglate and diatrizoate induced a comparable decrease in renal blood flow (RBF) (Figure 1). During the ischaemic period the effects of diatrizoate on renal haemodynamics were dramatically enhanced. Ioxaglate and iopamidol induced a 20±12 and a 32±9% decrease in RBF at 1 min respectively. Iopamidol and ioxaglate induced a mild increase in renal vascular resistance (RVR). Diatrizoate induced a 77±10% decrease in RBF and a maximum increase in RVR at 1 min from 0.9±0.09 to 26±12 mmHg min/ml. There was still a 36±14% and a 23±13% decrease in RBF 10 and 20 min after diatrizoate administration. These changes were significantly higher than those observed with all CM during the control period and LOCM during the ischaemic period. We have thus shown that ischaemia potentiates the renal vascular effect of contrast media. This experiment provides substantial support for the thesis according to which CM induced renal failure may be primarily caused by renal ischaemia. During ischaemia low osmolar contrast agents induced less vasocontriction and may therefore be particularly indicated in high risk patients.
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Nitric oxide, released from the kidney under basal conditions, has been shown to influence renal vascular resistance [15,16]. It has been shown that injection of CM induced nitric oxide release in rats [17]. Furthermore, nitric oxide blockade induces medullary vasoconstriction instead of the local vasodilatation observed in control animals after iothalamate administration [18]. During CM administration nitric oxide release may partially inhibit the decrease in RBF and GFR and protect the kidney against ischaemia, preferentially within the medulla.
We have demonstrated the involvement of nitric oxide and endothelin in radiographic contrast medium-induced changes in renal haemodynamics [19]. We have shown in the dog that CM induced a significant decrease in RBF and GFR and a significant increase in urinary endothelin excretion. L-Name enhanced the effect of CM on GFR and RBF. L-Arginine attenuated the effect of L-Name on the CM-induced reduction in GFR. These finding support the hypothesis that acute CM-induced intrarenal vasoconstriction may involve an imbalance of endothelial vasoactive agents, nitric oxide and endothelin.
During the past decade LOCM have become increasingly popular for radiographic procedures requiring intravascular contrast because they have been found to cause less discomfort and fewer cardiovascular and adverse anaphylactoid effects than HOCM. However, controversy continues about the need for universal use of LOCM because of their higher cost.
Renal tolerance of LOCM and non-ionic dimers
A major question concerning these new agents is their relative nephrotoxicity compared to HOCM. We have shown that the renal haemodynamic effects of contrast media are markedly enhanced by ischaemia. In this model the LOCM, ioxaglate and iopamidol induced significantly less renal vasoconstriction than HOCM, thus suggesting that they could be less nephrotoxic [13]. We have also tested the comparative renal tolerance of HOCM and LOCM in an in vivo rat model [20]. The objective of this study was first to develop a reproducible and reversible model of acute renal failure following CM infusion in the rat, and second to use that method to compare the nephrotoxicity of low and high osmolar contrast agents. CM or saline were perfused in the aorta while a clamp was applied on the aorta just above the renal artery. Three minutes of renal ischaemia with or without infusion of isotonic saline induced no change in serum creatinine and a slight and transient decrease in creatinine clearance at 24 h. Urinary N-acetyl glucosaminidase (NAG) excretion was not modified in this control group.
All 17 kidneys examined were normal. Hypertonic saline (2100 mosm/kg) induced a significant increase in serum creatinine and a significant decrease in creatinine clearance. Urinary NAG excretion increased significantly. Histologic analysis of five kidneys revealed mainly acute tubular necrosis.
Diatrizoate induced an acute and reversible renal failure. Histologic examination of seven kidneys revealed acute tubular necrosis (n=4), tubular cytoplasmic vacuolization (n=2) or no histologic abnormalities (n=1). In contrast ioxaglate and iopamidol induced no change in serum creatinine and a slight decrease in creatinine clearance comparable to that observed in the control group. Both compounds induced a significant increase in urinary NAG excretion at 24 h which was completely reversible at 48 h. Histological analysis of eight kidneys exposed to ioxaglate revealed tubular cytoplasmic vacuolization and no histologic abnormalities. Histolocal analysis of 10 kidneys exposed to iopamidol revealed tubular cytoplasmic vacuolization (n=8) and no histological abnormalities (n=2). In this model ionic and non ionic low osmolar contrast agents clearly were less nephrotoxic than high osmolar contrast agents.
Initially many clinical studies of the nephrotoxicity of CM have evaluated populations that were too small to exclude or establish reliably a reduction in nephrotoxicity with LOCM. We have compared the renal effects of ioxitalamate, ioxaglate and iopamidol in patients with chronic renal failure [21]. Sixty consecutive patients with an estimated creatinine clearance (ECRCl)<60 ml/min were randomly assigned to receive either ioxitalamate, iopamidol or ioxaglate. All patients received 500 cm3 isotonic saline before the procedure. Serum creatinine and creatinine clearance were estimated before, 1 and 2 or 3 days after the procedure. There was no statistical difference between the three groups with respect to age, sex, weight, renal function, amount of iodine, and type of procedure. Mean serum creatinine and ECRCl remained unchanged after administration of CM. No patient had nephrotoxicity or acute oliguria requiring dialysis as a result of the administration of CM. The number of patients with an increase in the serum creatinine level >10% from the vasal value did not differ in the treatment groups. The maximal increases in serum creatinine were 52 µmol/l (29%) in the ioxitalamate group, 56 µmol/l (18%) in the ioxaglate group and 57 µmol/l (23%) in the iopamidol group (P=NS). Using a population carefully randomized and matched for renal insufficiency, we could not show any differences in nephrotoxicity between these three contrast agents. Clinically serious renal impairment was uncommon in our study, regardless of the contrast agent used.
However, the interpretation of these favourable findings requires a cautionary note. All patients in this study were well hydrated before and after uro/ angiography, and non had a recent renal injury or treatment with a nephrotoxic agent that would predispose to injury from CM.
Furthermore, studies of substantial numbers of patients with pre-existng renal impairment have now been reported and the results of some of these trial have suggested that LOCM are less nephrotoxic than HOCM. Differences in nephrotoxicity between the two contrast groups were confined to patients with pre-existing renal insufficiency alone or combined with diabetes mellitus [22,23]. Those results were confirmed in a meta-analysis performed by Barret et al. on 45 trials.
Among 24 trials with available data, the mean change in serum creatinine was 0.2±6.2 µmol/l less with LOCM than with HOCM. Among 25 trials with available data the pooled adds of a rise in serum creatinine level of more than 44 µmol/l with LOCM was 0.61 times that after HOCM.
In contrast, in patients with normal renal function, regardless of the presence or absence if diabetes mellitus, LOCM are no less nephrotoxic than HOCM. It should be outlined that in subjects without renal insufficiency the incidence of contrast media induced acute renal failure is very low provided risk factors (such as dehydration) are detected and corrected. Additional studies in high-risk patients will be required to determine if LOCM are also associated with a reduced incidence of severe nephrotoxicity (e.g. that would require acute dialysis).
More recently non ionic dimers which are iso-osmotic with plasma have been introduced (iotrolan and iodixanol). While evidence for their real advantages compared with LOCM and HOCM are lacking they are already presented as an ideal physiological formulation. We have analysed the renal tolerance of non ionic dimers as assessed experimentally and clinically in the literature. Experimentally non ionic dimers may alter GFR and RBF in a fashion at least similar to LOCM. These alterations in renal haemodynamics may be due to an increase in blood viscosity and red blood cell aggregation. Animal data unequivocally show that non ionic dimers have equivalent effects on the kidney as do LOCM.
Furthermore, no randomized clinical trials have been carried out to show a difference in the renal tolerance between non ionic dimers and LOCM. Several observations of acute renal failure secondary to the administration of non ionic dimers have already been reported outlining the nephrotic potential of those new contrast media and clinically in the literature [24].
Finally, from the review of the literature and our studies it is clear that acute renal failure following the injection of contrast media remains a frequent and serious iatrogenic event. A better understanding of the pathophysiology of this complication will help in preventing this complication.
References