- Email: [email protected]
Iohexol Versus Iothalamate for GFR Measurement
Correspondence 6. Filiopoulos V, Hadjiyannakos D, Vlassopoulus D. Febuxostat renoprotection in CKD patients with asymptomatic hyperuricemia. Am J Kidney Dis. 2016;67(6):989-990. Ó 2016 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2016.04.001
Iohexol Versus Iothalamate for GFR Measurement To the Editor: We read with great interest the article by Seegmiller et al1 demonstrating different urinary clearances of iothalamate and iohexol. The authors speculate that the difference reflects nonideal behavior of iohexol as a glomerular filtration rate marker. However, the study does not include a comparison with inulin; thus, it remains uncertain which marker is less accurate in this respect. Because iohexol was less ultrafilterable across a 2,000-Da membrane, Seegmiller et al suggested that iohexol may be subject to a higher degree of protein binding. However, protein binding is reported to be ,2%,2-4 by itself unlikely to account for a 15% lower clearance compared to iothalamate. Iohexol differs from iothalamate in being nonionic, and active secretion of iohexol has to our knowledge not been demonstrated. In contrast, it is well documented that in several species, including humans, tubular transport of iothalamate and other ionic contrast media is concentration dependent (ie, transport increases at low concentrations).5,6 Because the subcutaneous administration used by Seegmiller et al likely resulted in very low plasma concentrations, tubular secretion of iothalamate is in our view a likely explanation for the different clearance rates found. We previously found equal renal clearances of iohexol and inulin using intravenous infusion of the markers with higher plasma concentrations.7 Thus, until the final comparison with inulin is done using intravenous infusion and urine sampling, it is our opinion that iohexol clearance may be closer to that of inulin than iothalamate. One final note for clarification: in contrast to how it is referenced in several places in Seegmiller et al,1 mean bias between iohexol and inulin renal clearances in Soveri et al8 is given in relative, not absolute, units (ie, as a percentage instead of in mL/min/1.73 m2). Gunnar Sterner, MD, PhD,1 Sten-Erik Bäck, MD, PhD2 Ulf Nyman, MD, PhD1 1 Skane University Hospital, Malmö, Sweden 2 Skane University Hospital, Lund, Sweden
Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Evaluated by the Editor-in-Chief.
assessment of glomerular filtration rate. J Lab Clin Med. 1984;104:955-961. 4. Skinnemoen K. Physiochemical properties and degree of protein binding of iopentol. Acta Radiol 1987;(suppl 370):33-36. 5. Odlind B, Hallengren R, Sohtell M, et al. Is 125I iothalamate an ideal marker for glomerular filtration? Kidney Int. 1985;27: 9-16. 6. Zurth C. Mechanism of renal excretion of various X-ray contrast materials in rabbits. Invest Radiol. 1984;19(2):110-115. 7. Sterner G, Frennby B, Mansson S, et al. Determining ‘true’ glomerular filtration rate in healthy adults using infusion of inulin and comparing it with values obtained using other clearance techniques or prediction equations. Scand J Urol Nephrol. 2008;42(3): 278-285. 8. Soveri I, Berg UB, Bjork J, et al. Measuring GFR: a systematic review. Am J Kidney Dis. 2014;64:411-424. Ó 2016 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.12.035
In Reply to ‘Iohexol Versus Iothalamate for GFR Measurement’ We welcome the comments and interest of Drs Sterner, Bäck, and Nyman1 regarding our study.2 We agree that until inulin is available again for studies of humans, it will be difficult to directly assess the comparable accuracy of iothalamate and iohexol in humans. Our study of 150 patients across a broad range of glomerular filtration rates (GFRs) showed a 15% difference in urinary clearance of iothalamate versus iohexol. Creatinine clearances were significantly greater than both iothalamate (by 24%) and iohexol (by 38%), suggesting that neither is likely to have a secretory component approaching creatinine. However, the dialyzability in vitro of iohexol versus iothalamate was less, which could have contributed to some of the observed clearance differences. We acknowledge the results cited in the letter of their own study3 comparing iohexol with inulin in 20 healthy individuals with normal GFRs. The dosing in their study was 1 to 2 orders of magnitude greater than in ours. Some of the published comparability discrepancy could be due to saturation or inhibition of mechanisms associated with different dosing. However, given the paucity of studies directly comparing renal clearance of iohexol with inulin, we believe it is premature to state with confidence whether one contrast agent is more accurate than the other. As mentioned in the editorial to our study,4 it is possible that the differences between iohexol and iothalamate renal clearances could reflect small, and opposite, biases with inulin. We also agree that explanations for the clearance differences would benefit from having inulin available for studies of humans. Timothy S. Larson, MD Mayo Clinic, Rochester, Minnesota Jesse Seegmiller, PhD University of Minnesota, Minneapolis, Minnesota
References 1. Seegmiller JC, Burns BE, Shinstock CA, et al. Discordance between iothalamate and iohexol urinary clearances. Am J Kidney Dis. 2016;67(1):49-55. 2. Omnipaque Summary of Product Characteristics. Medicine and Healthcare Products Regulatory Agency. January 2015. http://www. mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1437111492 902.pdf. Accessed November 30, 2015. 3. Krutzen E, Back SE, Nilsson-Ehle I, Nilsson-Ehle P. Plasma clearance of a new contrast agent, iohexol: a method for the Am J Kidney Dis. 2016;67(6):989-996
Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Evaluated by the Editor-in-Chief.
References 1. Sterner G, Bäck S-E, Nyman U. Iohexol versus iothalamate for GFR measurement. Am J Kidney Dis. 2016;67(6):991. 991
Iohexol Versus Iothalamate for GFR Measurement To the Editor: We read with great interest the article by Seegmiller et al1 demonstrating different urinary clearances of iothalamate and iohexol. The authors speculate that the difference reflects nonideal behavior of iohexol as a glomerular filtration rate marker. However, the study does not include a comparison with inulin; thus, it remains uncertain which marker is less accurate in this respect. Because iohexol was less ultrafilterable across a 2,000-Da membrane, Seegmiller et al suggested that iohexol may be subject to a higher degree of protein binding. However, protein binding is reported to be ,2%,2-4 by itself unlikely to account for a 15% lower clearance compared to iothalamate. Iohexol differs from iothalamate in being nonionic, and active secretion of iohexol has to our knowledge not been demonstrated. In contrast, it is well documented that in several species, including humans, tubular transport of iothalamate and other ionic contrast media is concentration dependent (ie, transport increases at low concentrations).5,6 Because the subcutaneous administration used by Seegmiller et al likely resulted in very low plasma concentrations, tubular secretion of iothalamate is in our view a likely explanation for the different clearance rates found. We previously found equal renal clearances of iohexol and inulin using intravenous infusion of the markers with higher plasma concentrations.7 Thus, until the final comparison with inulin is done using intravenous infusion and urine sampling, it is our opinion that iohexol clearance may be closer to that of inulin than iothalamate. One final note for clarification: in contrast to how it is referenced in several places in Seegmiller et al,1 mean bias between iohexol and inulin renal clearances in Soveri et al8 is given in relative, not absolute, units (ie, as a percentage instead of in mL/min/1.73 m2). Gunnar Sterner, MD, PhD,1 Sten-Erik Bäck, MD, PhD2 Ulf Nyman, MD, PhD1 1 Skane University Hospital, Malmö, Sweden 2 Skane University Hospital, Lund, Sweden
Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Evaluated by the Editor-in-Chief.
assessment of glomerular filtration rate. J Lab Clin Med. 1984;104:955-961. 4. Skinnemoen K. Physiochemical properties and degree of protein binding of iopentol. Acta Radiol 1987;(suppl 370):33-36. 5. Odlind B, Hallengren R, Sohtell M, et al. Is 125I iothalamate an ideal marker for glomerular filtration? Kidney Int. 1985;27: 9-16. 6. Zurth C. Mechanism of renal excretion of various X-ray contrast materials in rabbits. Invest Radiol. 1984;19(2):110-115. 7. Sterner G, Frennby B, Mansson S, et al. Determining ‘true’ glomerular filtration rate in healthy adults using infusion of inulin and comparing it with values obtained using other clearance techniques or prediction equations. Scand J Urol Nephrol. 2008;42(3): 278-285. 8. Soveri I, Berg UB, Bjork J, et al. Measuring GFR: a systematic review. Am J Kidney Dis. 2014;64:411-424. Ó 2016 by the National Kidney Foundation, Inc. http://dx.doi.org/10.1053/j.ajkd.2015.12.035
In Reply to ‘Iohexol Versus Iothalamate for GFR Measurement’ We welcome the comments and interest of Drs Sterner, Bäck, and Nyman1 regarding our study.2 We agree that until inulin is available again for studies of humans, it will be difficult to directly assess the comparable accuracy of iothalamate and iohexol in humans. Our study of 150 patients across a broad range of glomerular filtration rates (GFRs) showed a 15% difference in urinary clearance of iothalamate versus iohexol. Creatinine clearances were significantly greater than both iothalamate (by 24%) and iohexol (by 38%), suggesting that neither is likely to have a secretory component approaching creatinine. However, the dialyzability in vitro of iohexol versus iothalamate was less, which could have contributed to some of the observed clearance differences. We acknowledge the results cited in the letter of their own study3 comparing iohexol with inulin in 20 healthy individuals with normal GFRs. The dosing in their study was 1 to 2 orders of magnitude greater than in ours. Some of the published comparability discrepancy could be due to saturation or inhibition of mechanisms associated with different dosing. However, given the paucity of studies directly comparing renal clearance of iohexol with inulin, we believe it is premature to state with confidence whether one contrast agent is more accurate than the other. As mentioned in the editorial to our study,4 it is possible that the differences between iohexol and iothalamate renal clearances could reflect small, and opposite, biases with inulin. We also agree that explanations for the clearance differences would benefit from having inulin available for studies of humans. Timothy S. Larson, MD Mayo Clinic, Rochester, Minnesota Jesse Seegmiller, PhD University of Minnesota, Minneapolis, Minnesota
References 1. Seegmiller JC, Burns BE, Shinstock CA, et al. Discordance between iothalamate and iohexol urinary clearances. Am J Kidney Dis. 2016;67(1):49-55. 2. Omnipaque Summary of Product Characteristics. Medicine and Healthcare Products Regulatory Agency. January 2015. http://www. mhra.gov.uk/home/groups/spcpil/documents/spcpil/con1437111492 902.pdf. Accessed November 30, 2015. 3. Krutzen E, Back SE, Nilsson-Ehle I, Nilsson-Ehle P. Plasma clearance of a new contrast agent, iohexol: a method for the Am J Kidney Dis. 2016;67(6):989-996
Acknowledgements Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Evaluated by the Editor-in-Chief.
References 1. Sterner G, Bäck S-E, Nyman U. Iohexol versus iothalamate for GFR measurement. Am J Kidney Dis. 2016;67(6):991. 991