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Contrast media-induced nephrotoxicity: A new insight
Clinical Radiology (1997) 52, 573-574
Editorial Contrast Media-induced Nephrotoxicity: A New Insight The use of iodinated contrast media remains necessary for many diagnostic imaging examinations and in interventional cardiovascular procedures the administration of large doses is often required. Anaphylactoid reactions and cardiovascular instability are well recognized side-effects of the intravascular use of contrast media. However, contrast medium nephrotoxicity is a complication that is not widely appreciated even amongst some of the heavy users of contrast material. Fortunately, the problem is rare in patients with normal renal function [1,2], however, patients with renal insufficiency, particularly those suffering from diabetic nephropathy, are at high risk of nephrotoxicity [1,2]. Renal failure requiring dialysis has been reported in 15% of such patients despite adequate hydration and the use of low osmolar contrast agents [3]. Other important risk factors for the development of contrast nephropathy are severe congestive heart failure and the administration of a high dose of contrast medium [1,2]. The understanding of the mechanisms responsible for the reduction in renal function induced by contrast media has recently improved. Evidence is now accumulating to indicate that contrast media can increase the renal vascular resistance and decrease the glomerular filtration rate through direct effects on the kidney [4,5]. The pathophysiology of contrast media induced renal dysfunction involves the modulation of tubular regulatory mechanisms and the production of renal vasoactive mediators [ 1,2,6]. High osmolar contrast media induce significant diuresis and natriuresis which in turn may activate the tubuloglomerular feedback response leading to the constriction of glomerular afferent arterioles and a decrease in glomerular filtration rate [6]. The intrarenal production of vasoactive substances is also influenced by contrast media [1,2]. Nitric oxide and prostacyclin are vasodilators which are produced by the vascular endothelium [7]. Under normal physiological conditions, nitric oxide is released continuously and keeps the vasculature in a dilated state [7]. There is no evidence so far to suggest that contrast media increase the renal vascular resistance by reducing the synthesis of these vasodilators in the kidney directly. On the contrary, there are some observations indicating that contrast media may stimulate their production in the vulnerable region of the renal medulla [8]. The transport activity and therefore oxygen demand in the medullary thick ascending limb of loop of Henle increases in response to the osmotic load and natriuresis associated with contrast media administration [8,9]. In situations where there is a decrease in the synthesis of nitric oxide or prostaglandins in the kidney, the ischaemic and hypoxic insults of contrast media are accentuated because the protective vasodilatory effect of these mediators is lost [10,11]. Intrarenally formed adenosine seems to be involved in the pathogenesis of contrast media induced nephrotoxicity [ 12]. Adenosine is a mediator of the tubuloglomerular feedback response and can induce intrarenal vasoconstriction by its A1 receptor subtype [12,13]. The reduction in glomerular filtration rate induced by contrast media in dogs with renal Correspondence to: Dr S. K. Morcos, X-ray Department, Northern General Hospital, Sheffield $5 7AU, UK. © 1997 The Royal College of Radiologists.
insufficiency can be abolished by pre-treatment with either a selective A1 adenosine receptor antagonist or theophylline, a non-selective antagonist of the adenosine receptors [12]. Clinical experience, although limited, suggests that theophylline may have some protective effect against the renal impairment associated with contrast medium administration [13,14]. It is now becoming clear that the potent vasoconstrictor peptide endothelin is a vital mediator of the renal haemodynamic effects of contrast media [15-23]. In the kidney, endothelin produces changes similar to that observed with contrast media including vasoconstriction, decrease in glomerular filtration rate, natriuresis and diuresis [24]. The ability of contrast media to stimulate the production of endothelin has been demonstrated in several studies. Contrast media can stimulate the release of endothelin in endothelial cell culture [15]. Intravascular administration of contrast media induces an increase both in the plasma endothelin concentration and in urinary endothelin excretion rate in rats, dogs and humans [ 15,16,18,19]. Functional studies in vitro and in vivo have shown that endothelin receptor antagonists can prevent the reduction in glomerular filtration rate [20,21] and the vasoconstriction induced by contrast media in the kidney [17,20-22]. The relationship between endothelin and adenosine in mediating the renal haemodynamic effects of contrast media is not known. It is possible that the renal ischaemia and natriuresis produced by endothelin may lead to an increase in adenosine tissue levels within the kidney [ 13,23 ]. Further studies are required to define the biological interaction between these two important mediators. Several measures that are partly effective have been advocated for the prevention of contrast media induced nephrotoxicity. They include the use of low osmolar contrast agents, hydration and the prophylactic administration of theophylline or drugs that induce an increase in total renal blood flow such as calcium channel blockers, dopamine and atrial natriuretic peptide [24]. The latter two agents have failed to prevent the development of contrast media induced renal failure in patients with diabetic nephropathy [24]. The clinical effectiveness of calcium channel blockers and theophylline in the prevention of contrast induced renal impairment remains to be confirmed [24]. We believe that endothelin receptor antagonists present a new and rational approach to the prevention of contrast medium nephropathy. Orally active non-selective endothelin receptor antagonists are currently under development and in the near future may offer a better protection against this important complication. REFERENCES
1 BarrettBJ. Contrastnephrotoxicity.Journal of the American Socie~' of Nephrology 1993;5:125-137. 2 Porter GA. Radiocontrast-inducednephropathy.Nephrology, Dialysis. Transplantation 1994;9[suppl.]:146-156. 3 ManskeCL, SprafkaJM, StronyJT, Wang Y. Contrast nephropathyin azotemiediabeticpatientsundergoing coronaryangiography.American Journal of Medichw 1990;89:615-620. 4 Brown P, Haylor JL, Cope GH, E1 Nahas AM, Morcos SK. Effect of diatfizoate on the function of the isolated perfused rat kidney. British Journal of Radiology 1992;65:1011 1017.
574
CLINICAL RADIOLOGY
5 Brown P, Haylor JL, E1 Nahas AM, Morcos SK. The functional effects of contrast media on the isolated perfused rat kidney. Contributions to Nephrology 1993; 101:235-240. 6 Morcos SK, Brown PWG, Oldroyd S, E1 Nahas AM, Haylor J. Relationship between the diuretic effect of radiocontrast media and their ability to increaserenal vascular resistance. British Journal of Radiology 1995;68:850-853. 7 Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. The New England Journal of Medicine 1990;323: 27-36. 8 Agmon Y, Peleg H, Greenfield Z, Rosen S, Brezis M. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. Journal of Clinical bwestigations 1994;94:1069-1075. 9 Heyman SN, Rosen S, Brezis M. Radiocontrast nephropathy: a paradigm for synergism between toxic and hypoxic insults in the kidney. Experimental Nephrology 1994;2:153-157. 10 Brezis, M, Heyman, SN, Dinour D et al. Role of nitric oxide in renal medullary oxygenation, studies in isolated and intact rat kidneys. Journal of Clinical Investigations 1991 ;88:390-395. 11 Touati, C, Idee JM, Deray G e t al. Modulation of renal effects of contrast media by endothelium-derived nitric oxide in the rat. Investigative Radiology 1993;28:814-820. 12 Arakawa K, Suzuki H, Naitoh M e t al. Role of adenosine in the renal responses to contrast medium. Kidney International 1996;49:11991206. 13 Erley CM, Duda SH, Schlepckow S e t al. Adenosine antagonist theophylline prevents the reduction of glomemlar filtration rate after contrast media application. Kidney International 1994;45:1425 - 1431. 14 Katholi RE, Taylor GJ, McCann WP et al. Nephrotoxicity from contrast media: attenuation with theophylline. Radiology 1995:195:17-22. 15 Heyman SN, Clark BA, Kaiser N e t al. Radiocontrast agents induce endothelin release in vivo and in vitro. Journal of the American Society of Nephrology 1992;3:58-65. 16 Margulies KB, Hildebrand FLJ, Heublein DM, Burnett JCJ. Radio-
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contrast increases plasma and urinary endothelin. Journal of the American Society of Nephrology 1991;2:1041-1045. Cantley LG, Spokes K, Clark B, McMahon EG, Carter J, Epstein FH. Role of endothelin and prostaglandins in radiocontrast-induced renal artery constriction. Kidney International 1993;44:1217-1223. Heyman SN, Clark BA, Cantley L e t al. Effects of ioversol vs. iothalamate on endothelin release and radiocontrast nephropathy, h~vestigative Radiology 1993;28:313-318. Marguiles KB, McKinley LJ, Burnett JC. Endothelin in human and canine radiocontrast-induced nephropathy. Journal of Vascular Research 1992;29:163-164. Oldroyd S, Slee S J, Haylor J, Morcos SK, Wilson C. Role for endothelin in the renal response to radiocontrast media in the rat. Clinical Science 1994;87:427-424. Oldroyd SD, Haylor JL, Morcos SK. Bosentan, an orally active endothelin antagonist: effect on renal response to contrast media. Radiology 1995; 196:661-665. Brooks DP, Dennis Depalma P. Blockade of radiocontrast-induced nephrotoxicity by endothelin receptor antagonist, SB209670. Nephron 1996;72:629-636. Remuzzi, G, Benigni A. Endothelins in the control of cardiovascular and renal function. The Lancet 1993;342:589-593. Barrett B J, Parfrey PS. Prevention of nephrotoxicity induced by radiocontrast agents. The New England Journal of Medicine 1994;331: 1449-1450. S. K. M O R C O S , S. O L D R O Y D * a n d J. H A Y L O R *
D e p a r t m e n t o f Diagnostic Imaging and *Sheffield K i d n e y Institute, Northern General Hospital N H S Trust, Sheffield, U K
© 1997 The Royal College of Radiologists, ClinicalRadiology, 52, 573-574.
Editorial Contrast Media-induced Nephrotoxicity: A New Insight The use of iodinated contrast media remains necessary for many diagnostic imaging examinations and in interventional cardiovascular procedures the administration of large doses is often required. Anaphylactoid reactions and cardiovascular instability are well recognized side-effects of the intravascular use of contrast media. However, contrast medium nephrotoxicity is a complication that is not widely appreciated even amongst some of the heavy users of contrast material. Fortunately, the problem is rare in patients with normal renal function [1,2], however, patients with renal insufficiency, particularly those suffering from diabetic nephropathy, are at high risk of nephrotoxicity [1,2]. Renal failure requiring dialysis has been reported in 15% of such patients despite adequate hydration and the use of low osmolar contrast agents [3]. Other important risk factors for the development of contrast nephropathy are severe congestive heart failure and the administration of a high dose of contrast medium [1,2]. The understanding of the mechanisms responsible for the reduction in renal function induced by contrast media has recently improved. Evidence is now accumulating to indicate that contrast media can increase the renal vascular resistance and decrease the glomerular filtration rate through direct effects on the kidney [4,5]. The pathophysiology of contrast media induced renal dysfunction involves the modulation of tubular regulatory mechanisms and the production of renal vasoactive mediators [ 1,2,6]. High osmolar contrast media induce significant diuresis and natriuresis which in turn may activate the tubuloglomerular feedback response leading to the constriction of glomerular afferent arterioles and a decrease in glomerular filtration rate [6]. The intrarenal production of vasoactive substances is also influenced by contrast media [1,2]. Nitric oxide and prostacyclin are vasodilators which are produced by the vascular endothelium [7]. Under normal physiological conditions, nitric oxide is released continuously and keeps the vasculature in a dilated state [7]. There is no evidence so far to suggest that contrast media increase the renal vascular resistance by reducing the synthesis of these vasodilators in the kidney directly. On the contrary, there are some observations indicating that contrast media may stimulate their production in the vulnerable region of the renal medulla [8]. The transport activity and therefore oxygen demand in the medullary thick ascending limb of loop of Henle increases in response to the osmotic load and natriuresis associated with contrast media administration [8,9]. In situations where there is a decrease in the synthesis of nitric oxide or prostaglandins in the kidney, the ischaemic and hypoxic insults of contrast media are accentuated because the protective vasodilatory effect of these mediators is lost [10,11]. Intrarenally formed adenosine seems to be involved in the pathogenesis of contrast media induced nephrotoxicity [ 12]. Adenosine is a mediator of the tubuloglomerular feedback response and can induce intrarenal vasoconstriction by its A1 receptor subtype [12,13]. The reduction in glomerular filtration rate induced by contrast media in dogs with renal Correspondence to: Dr S. K. Morcos, X-ray Department, Northern General Hospital, Sheffield $5 7AU, UK. © 1997 The Royal College of Radiologists.
insufficiency can be abolished by pre-treatment with either a selective A1 adenosine receptor antagonist or theophylline, a non-selective antagonist of the adenosine receptors [12]. Clinical experience, although limited, suggests that theophylline may have some protective effect against the renal impairment associated with contrast medium administration [13,14]. It is now becoming clear that the potent vasoconstrictor peptide endothelin is a vital mediator of the renal haemodynamic effects of contrast media [15-23]. In the kidney, endothelin produces changes similar to that observed with contrast media including vasoconstriction, decrease in glomerular filtration rate, natriuresis and diuresis [24]. The ability of contrast media to stimulate the production of endothelin has been demonstrated in several studies. Contrast media can stimulate the release of endothelin in endothelial cell culture [15]. Intravascular administration of contrast media induces an increase both in the plasma endothelin concentration and in urinary endothelin excretion rate in rats, dogs and humans [ 15,16,18,19]. Functional studies in vitro and in vivo have shown that endothelin receptor antagonists can prevent the reduction in glomerular filtration rate [20,21] and the vasoconstriction induced by contrast media in the kidney [17,20-22]. The relationship between endothelin and adenosine in mediating the renal haemodynamic effects of contrast media is not known. It is possible that the renal ischaemia and natriuresis produced by endothelin may lead to an increase in adenosine tissue levels within the kidney [ 13,23 ]. Further studies are required to define the biological interaction between these two important mediators. Several measures that are partly effective have been advocated for the prevention of contrast media induced nephrotoxicity. They include the use of low osmolar contrast agents, hydration and the prophylactic administration of theophylline or drugs that induce an increase in total renal blood flow such as calcium channel blockers, dopamine and atrial natriuretic peptide [24]. The latter two agents have failed to prevent the development of contrast media induced renal failure in patients with diabetic nephropathy [24]. The clinical effectiveness of calcium channel blockers and theophylline in the prevention of contrast induced renal impairment remains to be confirmed [24]. We believe that endothelin receptor antagonists present a new and rational approach to the prevention of contrast medium nephropathy. Orally active non-selective endothelin receptor antagonists are currently under development and in the near future may offer a better protection against this important complication. REFERENCES
1 BarrettBJ. Contrastnephrotoxicity.Journal of the American Socie~' of Nephrology 1993;5:125-137. 2 Porter GA. Radiocontrast-inducednephropathy.Nephrology, Dialysis. Transplantation 1994;9[suppl.]:146-156. 3 ManskeCL, SprafkaJM, StronyJT, Wang Y. Contrast nephropathyin azotemiediabeticpatientsundergoing coronaryangiography.American Journal of Medichw 1990;89:615-620. 4 Brown P, Haylor JL, Cope GH, E1 Nahas AM, Morcos SK. Effect of diatfizoate on the function of the isolated perfused rat kidney. British Journal of Radiology 1992;65:1011 1017.
574
CLINICAL RADIOLOGY
5 Brown P, Haylor JL, E1 Nahas AM, Morcos SK. The functional effects of contrast media on the isolated perfused rat kidney. Contributions to Nephrology 1993; 101:235-240. 6 Morcos SK, Brown PWG, Oldroyd S, E1 Nahas AM, Haylor J. Relationship between the diuretic effect of radiocontrast media and their ability to increaserenal vascular resistance. British Journal of Radiology 1995;68:850-853. 7 Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. The New England Journal of Medicine 1990;323: 27-36. 8 Agmon Y, Peleg H, Greenfield Z, Rosen S, Brezis M. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. Journal of Clinical bwestigations 1994;94:1069-1075. 9 Heyman SN, Rosen S, Brezis M. Radiocontrast nephropathy: a paradigm for synergism between toxic and hypoxic insults in the kidney. Experimental Nephrology 1994;2:153-157. 10 Brezis, M, Heyman, SN, Dinour D et al. Role of nitric oxide in renal medullary oxygenation, studies in isolated and intact rat kidneys. Journal of Clinical Investigations 1991 ;88:390-395. 11 Touati, C, Idee JM, Deray G e t al. Modulation of renal effects of contrast media by endothelium-derived nitric oxide in the rat. Investigative Radiology 1993;28:814-820. 12 Arakawa K, Suzuki H, Naitoh M e t al. Role of adenosine in the renal responses to contrast medium. Kidney International 1996;49:11991206. 13 Erley CM, Duda SH, Schlepckow S e t al. Adenosine antagonist theophylline prevents the reduction of glomemlar filtration rate after contrast media application. Kidney International 1994;45:1425 - 1431. 14 Katholi RE, Taylor GJ, McCann WP et al. Nephrotoxicity from contrast media: attenuation with theophylline. Radiology 1995:195:17-22. 15 Heyman SN, Clark BA, Kaiser N e t al. Radiocontrast agents induce endothelin release in vivo and in vitro. Journal of the American Society of Nephrology 1992;3:58-65. 16 Margulies KB, Hildebrand FLJ, Heublein DM, Burnett JCJ. Radio-
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20
21
22
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contrast increases plasma and urinary endothelin. Journal of the American Society of Nephrology 1991;2:1041-1045. Cantley LG, Spokes K, Clark B, McMahon EG, Carter J, Epstein FH. Role of endothelin and prostaglandins in radiocontrast-induced renal artery constriction. Kidney International 1993;44:1217-1223. Heyman SN, Clark BA, Cantley L e t al. Effects of ioversol vs. iothalamate on endothelin release and radiocontrast nephropathy, h~vestigative Radiology 1993;28:313-318. Marguiles KB, McKinley LJ, Burnett JC. Endothelin in human and canine radiocontrast-induced nephropathy. Journal of Vascular Research 1992;29:163-164. Oldroyd S, Slee S J, Haylor J, Morcos SK, Wilson C. Role for endothelin in the renal response to radiocontrast media in the rat. Clinical Science 1994;87:427-424. Oldroyd SD, Haylor JL, Morcos SK. Bosentan, an orally active endothelin antagonist: effect on renal response to contrast media. Radiology 1995; 196:661-665. Brooks DP, Dennis Depalma P. Blockade of radiocontrast-induced nephrotoxicity by endothelin receptor antagonist, SB209670. Nephron 1996;72:629-636. Remuzzi, G, Benigni A. Endothelins in the control of cardiovascular and renal function. The Lancet 1993;342:589-593. Barrett B J, Parfrey PS. Prevention of nephrotoxicity induced by radiocontrast agents. The New England Journal of Medicine 1994;331: 1449-1450. S. K. M O R C O S , S. O L D R O Y D * a n d J. H A Y L O R *
D e p a r t m e n t o f Diagnostic Imaging and *Sheffield K i d n e y Institute, Northern General Hospital N H S Trust, Sheffield, U K
© 1997 The Royal College of Radiologists, ClinicalRadiology, 52, 573-574.