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Reply from the authors
Kidney International, Vol. 58 (2000), p. 2239
LETTERS TO THE EDITOR REFERENCES
Endothelin antagonism and contrast nephropathy To the Editor: Wang et al recently reported endothelin (ET) receptor antagonism to exacerbate, not inhibit, human contrast nephropathy [1]. However, we are concerned about both the receptor selectivity and dosage regimen of the ET antagonist employed. In healthy volunteers SB209670, a nonselective ET antagonist, produced a fourfold increase in immunoreactive plasma ET-1, mediated through antagonism of the ETB clearance receptor [2]. This effect is liable to potentiate or prolong the increase in plasma ET-1 induced by the contrast agent itself. In humans, only a 2.5-fold increase in plasma ET-1 is required to decrease GFR, an effect mediated through the ETA receptor [3]. The observation that contrast nephropathy was exacerbated in patients receiving SB209670 is not surprising and suggests the absence of functional ETA receptor antagonism by this drug. SB 209670 was administered by a 12-hour intravenous infusion providing acute receptor antagonism, but the drug would have been virtually undetectable in plasma when contrast nephropathy was determined from the 48hour serum creatinine [2]. The importance of sustained drug cover in preventing human contrast nephropathy has been demonstrated previously with the calcium antagonist nitrendipine. A protective response was obtained with a daily dose of 20 mg (3 days) while a single 20 mg dose administered prior to contrast injection was ineffective [4]. To study the effect of an ET receptor antagonist on contrast nephropathy, ET receptor antagonism should be sustained for at least 48 hours after contrast delivery. We believe that multiple dosing with an orally administered ETA selective antagonist should be clinically evaluated in the prevention of contrast nephropathy before abandoning the development of ET receptor antagonists in the treatment of acute renal failure. John L. Haylor and Sameh K. Morcos Sheffield, United Kingdom Correspondence to John Haylor, Sheffield Kidney Institute, Northern General Hospital, Sheffield S5 7AU, UK
2000 by the International Society of Nephrology
1. Wang A, Holcslaw T, Bashore TM, Freed MI, Miller D, Rudnick MR, Szerlip H, Thames MD, Davidson CJ, Shusterman N, Schwab SJ: Exacerbation of radiocontrast nephrotoxocity by endothelin receptor antagonism. Kidney Int 57:1675–1680, 2000 2. Freed MI, Wilson DE, Thompson KA, Harrui RZ, Ilson BE, Jorkasky D: Pharmacolinetics and pharmacodynamics of SB209670, an endothelin receptor antagonist: Effects on the regulation of renal vascular tone. Clin Pharm Ther 65:473–482, 1999 3. Kaasjager KAH, Shaw S, Koomans HA, Rabelink TJ: Role of endothelin receptor subtypes in the systemic and renal responses to ET-1 in humans. J Am Soc Nephrol 8:32–39, 1997 4. Carraro ML, Mancini W, Artero AM, Stacul F, Grotto M, Cova M, Faccini L: Dose effect of nitrendipine on urinary enzymes and microproteins following non-ionic radiocontrast administration. Nephrol Dial Transplant 11:444–448, 1996
Reply from the authors We appreciate the comments of Haylor and Morcos. Regarding the issue of the nonselective endothelin (ET) antagonist, SB209670, evaluated in our study [1], pharmacokinetic data confirmed that mean immunoreactive plasma ET-1 levels were higher in the patients treated with SB209670 compared to the placebo group. Plasma concentration of ET-1 was significantly increased throughout the 12-hour infusion of SB209670 and remained elevated at 24 hours compared to placebo. Thus, the exacerbation of contrast nephrotoxicity after treatment with a nonselective ET receptor antagonist may be due to increased plasma ET-1 concentrations. Whether a selective ETA receptor antagonist is effective for the prevention of contrast nephrotoxicity remains to be determined by a randomized clinical trial. Regarding the duration of treatment with SB209670, previous animal studies of contrast nephrotoxicity have found that plasma ET-1 concentration increased significantly within minutes of radiocontrast injection, but returned to baseline at 30 minutes after injection [2]. To date, no vasodilator agent has been found to prevent radiocontrast nephrotoxicity and the potential benefit of longer treatment before or after radiocontrast administration has not been explored for this clinical end point. Andrew Wang and Steven J. Schwab Durham, North Carolina, USA
REFERENCES 1. Wang A, Holcslaw T, Bashore TM, Freed MI, Miller D, Rudnick MR, Szerlip H, Thames MD, Davidson CJ, Shusterman N, Schwab SJ: Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 57:1675–1680, 2000 2. Heyman SN, Clark BA, Kaiser N, Spokes K, Rosen S, Brezis M, Epstein FH: Radiocontrast agents induce endothelin release in vivo and in vitro. J Am Soc Nephrol 3:58–65, 1992
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LETTERS TO THE EDITOR REFERENCES
Endothelin antagonism and contrast nephropathy To the Editor: Wang et al recently reported endothelin (ET) receptor antagonism to exacerbate, not inhibit, human contrast nephropathy [1]. However, we are concerned about both the receptor selectivity and dosage regimen of the ET antagonist employed. In healthy volunteers SB209670, a nonselective ET antagonist, produced a fourfold increase in immunoreactive plasma ET-1, mediated through antagonism of the ETB clearance receptor [2]. This effect is liable to potentiate or prolong the increase in plasma ET-1 induced by the contrast agent itself. In humans, only a 2.5-fold increase in plasma ET-1 is required to decrease GFR, an effect mediated through the ETA receptor [3]. The observation that contrast nephropathy was exacerbated in patients receiving SB209670 is not surprising and suggests the absence of functional ETA receptor antagonism by this drug. SB 209670 was administered by a 12-hour intravenous infusion providing acute receptor antagonism, but the drug would have been virtually undetectable in plasma when contrast nephropathy was determined from the 48hour serum creatinine [2]. The importance of sustained drug cover in preventing human contrast nephropathy has been demonstrated previously with the calcium antagonist nitrendipine. A protective response was obtained with a daily dose of 20 mg (3 days) while a single 20 mg dose administered prior to contrast injection was ineffective [4]. To study the effect of an ET receptor antagonist on contrast nephropathy, ET receptor antagonism should be sustained for at least 48 hours after contrast delivery. We believe that multiple dosing with an orally administered ETA selective antagonist should be clinically evaluated in the prevention of contrast nephropathy before abandoning the development of ET receptor antagonists in the treatment of acute renal failure. John L. Haylor and Sameh K. Morcos Sheffield, United Kingdom Correspondence to John Haylor, Sheffield Kidney Institute, Northern General Hospital, Sheffield S5 7AU, UK
2000 by the International Society of Nephrology
1. Wang A, Holcslaw T, Bashore TM, Freed MI, Miller D, Rudnick MR, Szerlip H, Thames MD, Davidson CJ, Shusterman N, Schwab SJ: Exacerbation of radiocontrast nephrotoxocity by endothelin receptor antagonism. Kidney Int 57:1675–1680, 2000 2. Freed MI, Wilson DE, Thompson KA, Harrui RZ, Ilson BE, Jorkasky D: Pharmacolinetics and pharmacodynamics of SB209670, an endothelin receptor antagonist: Effects on the regulation of renal vascular tone. Clin Pharm Ther 65:473–482, 1999 3. Kaasjager KAH, Shaw S, Koomans HA, Rabelink TJ: Role of endothelin receptor subtypes in the systemic and renal responses to ET-1 in humans. J Am Soc Nephrol 8:32–39, 1997 4. Carraro ML, Mancini W, Artero AM, Stacul F, Grotto M, Cova M, Faccini L: Dose effect of nitrendipine on urinary enzymes and microproteins following non-ionic radiocontrast administration. Nephrol Dial Transplant 11:444–448, 1996
Reply from the authors We appreciate the comments of Haylor and Morcos. Regarding the issue of the nonselective endothelin (ET) antagonist, SB209670, evaluated in our study [1], pharmacokinetic data confirmed that mean immunoreactive plasma ET-1 levels were higher in the patients treated with SB209670 compared to the placebo group. Plasma concentration of ET-1 was significantly increased throughout the 12-hour infusion of SB209670 and remained elevated at 24 hours compared to placebo. Thus, the exacerbation of contrast nephrotoxicity after treatment with a nonselective ET receptor antagonist may be due to increased plasma ET-1 concentrations. Whether a selective ETA receptor antagonist is effective for the prevention of contrast nephrotoxicity remains to be determined by a randomized clinical trial. Regarding the duration of treatment with SB209670, previous animal studies of contrast nephrotoxicity have found that plasma ET-1 concentration increased significantly within minutes of radiocontrast injection, but returned to baseline at 30 minutes after injection [2]. To date, no vasodilator agent has been found to prevent radiocontrast nephrotoxicity and the potential benefit of longer treatment before or after radiocontrast administration has not been explored for this clinical end point. Andrew Wang and Steven J. Schwab Durham, North Carolina, USA
REFERENCES 1. Wang A, Holcslaw T, Bashore TM, Freed MI, Miller D, Rudnick MR, Szerlip H, Thames MD, Davidson CJ, Shusterman N, Schwab SJ: Exacerbation of radiocontrast nephrotoxicity by endothelin receptor antagonism. Kidney Int 57:1675–1680, 2000 2. Heyman SN, Clark BA, Kaiser N, Spokes K, Rosen S, Brezis M, Epstein FH: Radiocontrast agents induce endothelin release in vivo and in vitro. J Am Soc Nephrol 3:58–65, 1992
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