- Email: [email protected]
Contrast medium-induced nephropathy: The pathophysiology
http://www.kidney-international.org & 2006 International Society of Nephrology
Contrast medium-induced nephropathy: The pathophysiology PB Persson1 and M Tepel2 1
Institute of Physiology, Humboldt University Berlin, Berlin, Germany and 2Department of Nephrology, Free University Berlin, Berlin, Germany
A widespread, rather general, definition of contrast-induced nephropathy (CIN) is an impairment in renal function occurring within 3 days following the intravascular administration of contrast media (CM) and the absence of an alternative aetiology. In spite of the vast clinical importance of CIN, its understanding and the pathophysiology behind CIN remain incomplete. Many studies have been performed; however, they have provided no widely accepted conclusion so far. Here the possible mechanisms underlying CIN are outlined, which span from altered rheological properties, perturbation of renal haemodynamics, regional hypoxia, auto-, and paracrine factors (adenosine, endothelin, reactive oxygen species) to direct cytotoxic effects. Although these potential mediators of CIN will be discussed separately, several factors may act in concert to perturb kidney function after exposure to contrast media. From the current knowledge of the mechanisms causing CIN, it is not possible to recommend a certain class of contrast media, except to avoid large doses of CM of the first generation. From a pathophysiological perspective, volume expansion is effective in avoiding CIN, since water permeability of the collecting ducts will decrease and enhance fluid excretion. Hence, CM in the distal portions of the tubular system is diluted, which implies reduced fluid viscosity and a lower risk of obstruction. Kidney International (2006) 69, S8–S10. doi:10.1038/sj.ki.5000367 KEYWORDS: contrast induced nephropathy; contrast agents
Correspondence: PB Persson, Institut fu¨r Vegetative Physiologie, Humboldt Universita¨t, Medizinische Fakulta¨t (Charite´), Tucholsky str. 2, 10117 Berlin, Germany. E-mail: [email protected] S8
It is not fully clear what mechanisms cause contrast-induced nephropathy (CIN). Several suggestions have been put forward1 and it is widely held that a combination of various mechanisms needs to act in concert to cause CIN.2 Among these mechanisms, a reduction in renal perfusion3 caused by a direct effect of contrast media (CM) on the kidney and toxic effects on the tubular cells are generally recognized as important. However, the pathophysiological relevance of direct effects of CM on tubular cells remains disputed,2 as are the other proposed aetiologies. Among the often-discussed mechanisms, superoxide and perhaps other reactive oxygen species (ROS) have been discussed to promote CIN. Oxygen radicals are endogenously produced and levels can increase during oxidative stress. The most common oxygen radicals are superoxide (O2 ), hydrogen peroxide (H2O2) and hydroxyl radical (OH ).4 O2 and OH are more reactive than H2O2, which is not a radical, but exhibits a greater membrane permeability. O2 rapidly scavenges nitric oxide (NO) and could therefore blunt NO activity in the renal microvasculature. Since NO inhibits oxygen consumption, it is tempting to speculate that reduced (scavenged) NO during diabetes elevates oxygen consumption, thereby leading to reduced partial oxygen pressure values with consequences for endothelial–epithelial structure and function. ROS may play a role in the effects of various vasoconstrictors that have been considered important for the development of CIN. Since ROS are extracellular signalling molecules, they may be significant in mediating the actions of vasoconstrictors, such as angiotensin II, thromboxane A2, endothelin (ET)-1, adenosine, and norepinephrine. The adverse effects of CM on renal function may therefore involve the generation of ROS, for example, via adenosine formation. This notion is supported by experiments in which the generation of ROS was inhibited by allopurinol, or the amount of ROS was reduced by O2 dismutase. In these models, CM-induced reductions in glomerular filtration rate are attenuated.5 Later studies performed in humans further underscore a role of ROS in CIN.6 In these models, CMinduced reductions in glomerular filtration rate are attenuated.5 Taking the evidence for a role of ROS in CIN into account, it is not surprising that clinical trials have been performed with the aim to ameliorate CIN by scavenging ROS.7–11 Kidney International (2006) 69, S8–S10
PB Persson and M Tepel: CIN pathophysiology
Since ROS are extracellular signalling molecules, they may also be significant in mediating the part of the ET effects. The effect of ET on vascular beds is very dependent upon the receptor subtype activation. Two receptors have been identified: ET-A receptor elicits pronounced vasoconstriction, whereas the ET-B receptor has the opposite effect. The latter likely involves ET-dependent NO release. The net vasoactive response to ET is believed to vary depending on the vascular bed in question. A potential beneficial effect of ET in preventing CIN may be mediated by the ET-B-mediated effects, such as vasorelaxation. Thus, a selective ET-A receptor blockade could prove to be effective in the prevention of CIN. Indeed, a positive effect of ET-A selective blockade on the renal outer medullary hypoxic response to CM has been reported in the normal rat.12 However, when both ET-A and ET-B receptors are blocked in humans receiving CM, serum creatinine concentration rises to a greater extent than in patients receiving placebo, and the CIN incidence is significantly increased in the patients who received combined ET-A and ET-B blockade.13 CM can also have direct cytotoxic effects on renal tubular cells (Figure 1a and b). A perturbation of mitochondrial enzyme activity and mitochondrial membrane potential is found under ex vivo conditions in a proximal tubule cell
100 75 50 25 0
Iopamidol Iomeprol Iodixanol Ioxaglate Diatrizoate 25 100 50 75 Contrast media (mg I/ml)
MTT (% of control)
b 150
125
Iodixanol Iotrolan Iomeprol-300 Ioversol Ioxithalamate
100
50
* 250 *
0
25 50 75 Concentration (mg I/ml)
100
Figure 1 | Mitochondrial function in a proximal tubular cell line is impaired after 24-h treatment of contrast media (CM). Function was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction. (a) The comparison of the effects of various CM on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction reveal significant differences from one another (Po0.01) in the pioneer study by Hardieck et al.14 The least influence was found by the low-osmolality agents, followed by the iso-osmolality CM (Iodixanol). The ionic substances showed the greatest effect. (b) Heinrich et al.21 discovered no significant differences between the dimers and the low-osmolality monomers. However, ioxithalamate caused a significantly greater reduction in 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide. Kidney International (2006) 69, S8–S10
200 Viscosity (c.p.s)
MTT reduction (% of control)
a 125
line.14 Notably, low-osmolality monomeric CM cause less damage than iso-osmolality dimeric CM and ionic compounds reveal the most profound effect.14 In the more distal segments of the kidney, CM can cause apoptosis, as indicated in another cell line model.15 Apoptosis may be brought about by hypoxic damage16 and by a direct influence on these cells.15 The kidney region that is at particular risk for hypoxic damage is the deeper portion of the outer medulla. The vasa recta supplying the renal medulla with blood are distant, in spite of the relatively high oxygen requirements in this region due to salt reabsorption. It is this section of the kidney where the limbs of the loop of Henle exhibit hypoxic damage, as seen during perfusion with erythrocyte-free solution.17 By adding CM to the perfusate of the kidney, hypoxic injury to the region at risk is enhanced, probably by increasing renal vascular resistance.18 Remarkably, the isoosmolality CM iotrolan was found to impair local partial oxygen pressure values to a greater extent than the lowosmolality CM iopromide.19 A quite simple mechanism that seems to be of paramount importance for the development of CIN has hitherto attracted rather little attention: the rhelogical properties of CM. When the viscosity of the iso-osmolality dimers is taken into account, it is clear that iso-osmolality CM are not a priori superior to low-osmolality agents. Iso-osmolality CM may impair renal medullary blood flow to a greater extent than low-osmolality agents by virtue of their high viscosity. This indeed seems to be the case, as indicated by the particularly reduced partial oxygen pressure value levels caused by iso-osmolality CM.19 Augmented fluid viscosity caused by dimeric iso-osmolality CM may be of even more importance in the renal tubule. Under normal conditions, tubular fluid is of lower viscosity than plasma, as the ultrafiltrate contains very few plasma proteins. Use of dimeric iso-osmolality CM will increase tubular fluid viscosity dramatically (Figure 2) and thereby increase the resistance to flow in renal tubules.20 In consequence, renal interstitial pressure may take on values as high as 50 mmHg. Such pressure will dramatically decrease renal medullary flow and decrease glomerular filtration rate. Iotrolan Ioxaglate Iohexol Diatrizoate
150 100 50 0
10
20 30 Time (min)
40
50
Figure 2 | An iso-osmolality and highly viscous dimer, Iotrolan, increases urine viscosity to a considerably greater degree than ionic and monomeric contrast media. With permission from Ueda et al.22 S9
PB Persson and M Tepel: CIN pathophysiology
CONCLUSIONS
The current understanding of CIN development now includes the rheological properties of a fluid. Resistance depends on fluid viscosity, not osmolality (Poiseuille’s law). Thus, perhaps too much attention has been directed to the osmolality of different CM, while neglecting the impact of other physicochemical properties.
11.
12.
13.
14.
REFERENCES 1. Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium induced nephropathy. Kidney Int 2005; 68: 14–22. 2. Thomsen HS, Morcos SK. Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines. Br J Radiol 2003; 76: 513–518. 3. Solomon R. Radiocontrast-induced nephropathy. Semin Nephrol 1998; 18: 551–557. 4. Schnackenberg CG. Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature. Am J Physiol Regul Integr Comp Physiol 2002; 282: R335–R342. 5. Bakris GL, Lass N, Gaber AO et al. Radiocontrast medium-induced declines in renal function: a role for oxygen free radicals. Am J Physiol 1990; 258: F115–F120. 6. Katholi RE, Woods Jr WT, Taylor GJ et al. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis 1998; 32: 64–71. 7. Tepel M, van der GM, Schwarzfeld C et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180–184. 8. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. Acetylcysteine to prevent angiography-related renal tissue injury (the APART trial). Am J Cardiol 2002; 89: 356–358. 9. Briguori C, Manganelli F, Scarpato P et al. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2002; 40: 298–303. 10. Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 2002; 40: 1383–1388.
S10
15.
16.
17.
18. 19.
20.
21.
22.
Allaqaband S, Tumuluri R, Malik AM et al. Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv 2002; 57: 279–283. Liss P, Carlsson PO, Nygren A et al. Et-A receptor antagonist BQ123 prevents radiocontrast media-induced renal medullary hypoxia. Acta Radiol 2003; 44: 111–117. Wang A, Holcslaw T, Bashore TM et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000; 57: 1675–1680. Hardiek K, Katholi RE, Ramkumar V et al. Proximal tubule cell response to radiographic contrast media. Am J Physiol Renal Physiol 2001; 280: F61–F70. Hizoh I, Strater J, Schick CS et al. Radiocontrast-induced DNA fragmentation of renal tubular cells in vitro: role of hypertonicity. Nephrol Dial Transplant 1998; 13: 911–918. Beeri R, Symon Z, Brezis M et al. Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys. Kidney Int 1995; 47: 1806–1810. Brezis M, Rosen S, Silva P et al. Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney. J Clin Invest 1984; 73: 182–190. Heyman SN, Brezis M, Reubinoff CA et al. Acute renal failure with selective medullary injury in the rat. J Clin Invest 1988; 82: 401–412. Liss P, Nygren A, Erikson U et al. Injection of low and iso-osmolality contrast medium decreases oxygen tension in the renal medulla. Kidney Int 1998; 53: 698–702. Ueda J, Nygren A, Hansell P et al. Influence of contrast media on single nephron glomerular filtration rate in rat kidney. A comparison between diatrizoate, iohexol, ioxaglate, and iotrolan. Acta Radiol 1992; 33: 596–599. Heinrich MC, Kuhlmann MK, Grgic A et al. Cytotoxic effects of ionic high-osmolality, nonionic monomeric, and nonionic iso-osmolality dimeric iodinated contrast media on renal tubular cells in vitro. Radiology 2005; 235: 843–849. Ueda J, Nygren A, Sjoquist M et al. Iodine concentrations in the rat kidney measured by X-ray microanalysis. Comparison of concentrations and viscosities in the proximal tubules and renal pelvis after intravenous injections of contrast media. Acta Radiol 1998; 39: 90–95.
Kidney International (2006) 69, S8–S10
Contrast medium-induced nephropathy: The pathophysiology PB Persson1 and M Tepel2 1
Institute of Physiology, Humboldt University Berlin, Berlin, Germany and 2Department of Nephrology, Free University Berlin, Berlin, Germany
A widespread, rather general, definition of contrast-induced nephropathy (CIN) is an impairment in renal function occurring within 3 days following the intravascular administration of contrast media (CM) and the absence of an alternative aetiology. In spite of the vast clinical importance of CIN, its understanding and the pathophysiology behind CIN remain incomplete. Many studies have been performed; however, they have provided no widely accepted conclusion so far. Here the possible mechanisms underlying CIN are outlined, which span from altered rheological properties, perturbation of renal haemodynamics, regional hypoxia, auto-, and paracrine factors (adenosine, endothelin, reactive oxygen species) to direct cytotoxic effects. Although these potential mediators of CIN will be discussed separately, several factors may act in concert to perturb kidney function after exposure to contrast media. From the current knowledge of the mechanisms causing CIN, it is not possible to recommend a certain class of contrast media, except to avoid large doses of CM of the first generation. From a pathophysiological perspective, volume expansion is effective in avoiding CIN, since water permeability of the collecting ducts will decrease and enhance fluid excretion. Hence, CM in the distal portions of the tubular system is diluted, which implies reduced fluid viscosity and a lower risk of obstruction. Kidney International (2006) 69, S8–S10. doi:10.1038/sj.ki.5000367 KEYWORDS: contrast induced nephropathy; contrast agents
Correspondence: PB Persson, Institut fu¨r Vegetative Physiologie, Humboldt Universita¨t, Medizinische Fakulta¨t (Charite´), Tucholsky str. 2, 10117 Berlin, Germany. E-mail: [email protected] S8
It is not fully clear what mechanisms cause contrast-induced nephropathy (CIN). Several suggestions have been put forward1 and it is widely held that a combination of various mechanisms needs to act in concert to cause CIN.2 Among these mechanisms, a reduction in renal perfusion3 caused by a direct effect of contrast media (CM) on the kidney and toxic effects on the tubular cells are generally recognized as important. However, the pathophysiological relevance of direct effects of CM on tubular cells remains disputed,2 as are the other proposed aetiologies. Among the often-discussed mechanisms, superoxide and perhaps other reactive oxygen species (ROS) have been discussed to promote CIN. Oxygen radicals are endogenously produced and levels can increase during oxidative stress. The most common oxygen radicals are superoxide (O2 ), hydrogen peroxide (H2O2) and hydroxyl radical (OH ).4 O2 and OH are more reactive than H2O2, which is not a radical, but exhibits a greater membrane permeability. O2 rapidly scavenges nitric oxide (NO) and could therefore blunt NO activity in the renal microvasculature. Since NO inhibits oxygen consumption, it is tempting to speculate that reduced (scavenged) NO during diabetes elevates oxygen consumption, thereby leading to reduced partial oxygen pressure values with consequences for endothelial–epithelial structure and function. ROS may play a role in the effects of various vasoconstrictors that have been considered important for the development of CIN. Since ROS are extracellular signalling molecules, they may be significant in mediating the actions of vasoconstrictors, such as angiotensin II, thromboxane A2, endothelin (ET)-1, adenosine, and norepinephrine. The adverse effects of CM on renal function may therefore involve the generation of ROS, for example, via adenosine formation. This notion is supported by experiments in which the generation of ROS was inhibited by allopurinol, or the amount of ROS was reduced by O2 dismutase. In these models, CM-induced reductions in glomerular filtration rate are attenuated.5 Later studies performed in humans further underscore a role of ROS in CIN.6 In these models, CMinduced reductions in glomerular filtration rate are attenuated.5 Taking the evidence for a role of ROS in CIN into account, it is not surprising that clinical trials have been performed with the aim to ameliorate CIN by scavenging ROS.7–11 Kidney International (2006) 69, S8–S10
PB Persson and M Tepel: CIN pathophysiology
Since ROS are extracellular signalling molecules, they may also be significant in mediating the part of the ET effects. The effect of ET on vascular beds is very dependent upon the receptor subtype activation. Two receptors have been identified: ET-A receptor elicits pronounced vasoconstriction, whereas the ET-B receptor has the opposite effect. The latter likely involves ET-dependent NO release. The net vasoactive response to ET is believed to vary depending on the vascular bed in question. A potential beneficial effect of ET in preventing CIN may be mediated by the ET-B-mediated effects, such as vasorelaxation. Thus, a selective ET-A receptor blockade could prove to be effective in the prevention of CIN. Indeed, a positive effect of ET-A selective blockade on the renal outer medullary hypoxic response to CM has been reported in the normal rat.12 However, when both ET-A and ET-B receptors are blocked in humans receiving CM, serum creatinine concentration rises to a greater extent than in patients receiving placebo, and the CIN incidence is significantly increased in the patients who received combined ET-A and ET-B blockade.13 CM can also have direct cytotoxic effects on renal tubular cells (Figure 1a and b). A perturbation of mitochondrial enzyme activity and mitochondrial membrane potential is found under ex vivo conditions in a proximal tubule cell
100 75 50 25 0
Iopamidol Iomeprol Iodixanol Ioxaglate Diatrizoate 25 100 50 75 Contrast media (mg I/ml)
MTT (% of control)
b 150
125
Iodixanol Iotrolan Iomeprol-300 Ioversol Ioxithalamate
100
50
* 250 *
0
25 50 75 Concentration (mg I/ml)
100
Figure 1 | Mitochondrial function in a proximal tubular cell line is impaired after 24-h treatment of contrast media (CM). Function was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction. (a) The comparison of the effects of various CM on 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction reveal significant differences from one another (Po0.01) in the pioneer study by Hardieck et al.14 The least influence was found by the low-osmolality agents, followed by the iso-osmolality CM (Iodixanol). The ionic substances showed the greatest effect. (b) Heinrich et al.21 discovered no significant differences between the dimers and the low-osmolality monomers. However, ioxithalamate caused a significantly greater reduction in 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide. Kidney International (2006) 69, S8–S10
200 Viscosity (c.p.s)
MTT reduction (% of control)
a 125
line.14 Notably, low-osmolality monomeric CM cause less damage than iso-osmolality dimeric CM and ionic compounds reveal the most profound effect.14 In the more distal segments of the kidney, CM can cause apoptosis, as indicated in another cell line model.15 Apoptosis may be brought about by hypoxic damage16 and by a direct influence on these cells.15 The kidney region that is at particular risk for hypoxic damage is the deeper portion of the outer medulla. The vasa recta supplying the renal medulla with blood are distant, in spite of the relatively high oxygen requirements in this region due to salt reabsorption. It is this section of the kidney where the limbs of the loop of Henle exhibit hypoxic damage, as seen during perfusion with erythrocyte-free solution.17 By adding CM to the perfusate of the kidney, hypoxic injury to the region at risk is enhanced, probably by increasing renal vascular resistance.18 Remarkably, the isoosmolality CM iotrolan was found to impair local partial oxygen pressure values to a greater extent than the lowosmolality CM iopromide.19 A quite simple mechanism that seems to be of paramount importance for the development of CIN has hitherto attracted rather little attention: the rhelogical properties of CM. When the viscosity of the iso-osmolality dimers is taken into account, it is clear that iso-osmolality CM are not a priori superior to low-osmolality agents. Iso-osmolality CM may impair renal medullary blood flow to a greater extent than low-osmolality agents by virtue of their high viscosity. This indeed seems to be the case, as indicated by the particularly reduced partial oxygen pressure value levels caused by iso-osmolality CM.19 Augmented fluid viscosity caused by dimeric iso-osmolality CM may be of even more importance in the renal tubule. Under normal conditions, tubular fluid is of lower viscosity than plasma, as the ultrafiltrate contains very few plasma proteins. Use of dimeric iso-osmolality CM will increase tubular fluid viscosity dramatically (Figure 2) and thereby increase the resistance to flow in renal tubules.20 In consequence, renal interstitial pressure may take on values as high as 50 mmHg. Such pressure will dramatically decrease renal medullary flow and decrease glomerular filtration rate. Iotrolan Ioxaglate Iohexol Diatrizoate
150 100 50 0
10
20 30 Time (min)
40
50
Figure 2 | An iso-osmolality and highly viscous dimer, Iotrolan, increases urine viscosity to a considerably greater degree than ionic and monomeric contrast media. With permission from Ueda et al.22 S9
PB Persson and M Tepel: CIN pathophysiology
CONCLUSIONS
The current understanding of CIN development now includes the rheological properties of a fluid. Resistance depends on fluid viscosity, not osmolality (Poiseuille’s law). Thus, perhaps too much attention has been directed to the osmolality of different CM, while neglecting the impact of other physicochemical properties.
11.
12.
13.
14.
REFERENCES 1. Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium induced nephropathy. Kidney Int 2005; 68: 14–22. 2. Thomsen HS, Morcos SK. Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines. Br J Radiol 2003; 76: 513–518. 3. Solomon R. Radiocontrast-induced nephropathy. Semin Nephrol 1998; 18: 551–557. 4. Schnackenberg CG. Physiological and pathophysiological roles of oxygen radicals in the renal microvasculature. Am J Physiol Regul Integr Comp Physiol 2002; 282: R335–R342. 5. Bakris GL, Lass N, Gaber AO et al. Radiocontrast medium-induced declines in renal function: a role for oxygen free radicals. Am J Physiol 1990; 258: F115–F120. 6. Katholi RE, Woods Jr WT, Taylor GJ et al. Oxygen free radicals and contrast nephropathy. Am J Kidney Dis 1998; 32: 64–71. 7. Tepel M, van der GM, Schwarzfeld C et al. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343: 180–184. 8. Diaz-Sandoval LJ, Kosowsky BD, Losordo DW. Acetylcysteine to prevent angiography-related renal tissue injury (the APART trial). Am J Cardiol 2002; 89: 356–358. 9. Briguori C, Manganelli F, Scarpato P et al. Acetylcysteine and contrast agent-associated nephrotoxicity. J Am Coll Cardiol 2002; 40: 298–303. 10. Shyu KG, Cheng JJ, Kuan P. Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure. J Am Coll Cardiol 2002; 40: 1383–1388.
S10
15.
16.
17.
18. 19.
20.
21.
22.
Allaqaband S, Tumuluri R, Malik AM et al. Prospective randomized study of N-acetylcysteine, fenoldopam, and saline for prevention of radiocontrast-induced nephropathy. Catheter Cardiovasc Interv 2002; 57: 279–283. Liss P, Carlsson PO, Nygren A et al. Et-A receptor antagonist BQ123 prevents radiocontrast media-induced renal medullary hypoxia. Acta Radiol 2003; 44: 111–117. Wang A, Holcslaw T, Bashore TM et al. Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 2000; 57: 1675–1680. Hardiek K, Katholi RE, Ramkumar V et al. Proximal tubule cell response to radiographic contrast media. Am J Physiol Renal Physiol 2001; 280: F61–F70. Hizoh I, Strater J, Schick CS et al. Radiocontrast-induced DNA fragmentation of renal tubular cells in vitro: role of hypertonicity. Nephrol Dial Transplant 1998; 13: 911–918. Beeri R, Symon Z, Brezis M et al. Rapid DNA fragmentation from hypoxia along the thick ascending limb of rat kidneys. Kidney Int 1995; 47: 1806–1810. Brezis M, Rosen S, Silva P et al. Selective vulnerability of the medullary thick ascending limb to anoxia in the isolated perfused rat kidney. J Clin Invest 1984; 73: 182–190. Heyman SN, Brezis M, Reubinoff CA et al. Acute renal failure with selective medullary injury in the rat. J Clin Invest 1988; 82: 401–412. Liss P, Nygren A, Erikson U et al. Injection of low and iso-osmolality contrast medium decreases oxygen tension in the renal medulla. Kidney Int 1998; 53: 698–702. Ueda J, Nygren A, Hansell P et al. Influence of contrast media on single nephron glomerular filtration rate in rat kidney. A comparison between diatrizoate, iohexol, ioxaglate, and iotrolan. Acta Radiol 1992; 33: 596–599. Heinrich MC, Kuhlmann MK, Grgic A et al. Cytotoxic effects of ionic high-osmolality, nonionic monomeric, and nonionic iso-osmolality dimeric iodinated contrast media on renal tubular cells in vitro. Radiology 2005; 235: 843–849. Ueda J, Nygren A, Sjoquist M et al. Iodine concentrations in the rat kidney measured by X-ray microanalysis. Comparison of concentrations and viscosities in the proximal tubules and renal pelvis after intravenous injections of contrast media. Acta Radiol 1998; 39: 90–95.
Kidney International (2006) 69, S8–S10