Introduction
We showed neuroprotective and renoprotective effects of recombinant human erythropoietin (rhEPO) after kidney and spinal cord ischemia/reperfusion (I/R) injury [1, 2], but clinical studies using rhEPO to prevent acute kidney injury yielded equivocal results [3, 4]. Increased cytokine release and/or oxidative stress can cause EPO resistance due to receptor modification and/or downregulation [5]. Since we recently failed to confirm rhEPO-related kidney protection in atherosclerotic swine [6], we compared kidney EPO receptor expression in swine strains with and without pre-existing vascular disease and kidney dysfunction.
Methods
EPO receptor expression was quantified with immunohistochemistry (densitometric image analysis) of formalin-fixed paraffin sections from pre-injury kidney biopsies taken in young and healthy pigs (German Landrace, up to now n = 4) as well as swine (FBM strain, up to now n = 6) with familial hypercholesteremia (11.1 (7.4; 12.3) vs. 1.4 (1.3; 1.5) mmol/l, P < 0.001, n = 20 and 15, respectively, P < 0.001) and consecutive, diet-induced atherosclerosis [7].
Results
Atherosclerotic swine presented with reduced glomerular filtration rate (creatinine clearance 76 (60; 83) vs. 103 (79; 120) ml/minute, n = 19 each, P = 0.004) and chronic histological kidney injury (dilatation of Bowman's space, swelling of Bowman's capsule, tubular dilatation and necrosis). EPO receptor expression was reduced by nearly two orders of magnitude in this strain (94.6 (8.3; 112.5)×107 vs. 1.7 (0.0; 4.7) ×107 densitometric units, P = 0.010).
Conclusion
Even pretreatment with rhEPO did not influence I/R-induced acute kidney in swine with pre-existing impairment of kidney function and histological damage. The lacking beneficial effect of rhEPO was most likely due to the reduced expression of the EPO receptor, which may also explain contradictory results in clinical trials due to the frequent underlying kidney disease in the patients recruited.
References
Simon F, et al.: Crit Care Med. 2008, 36: 2143-2150. 10.1097/CCM.0b013e31817d7912
Simon F, et al.: Intensive Care Med. 2011, 37: 1525-1533. 10.1007/s00134-011-2303-4
Song YS, et al.: Am J Nephrol. 2009, 30: 253-260. 10.1159/000223229
Endre ZH, et al.: Kidney Int. 2010, 77: 1020-1030. 10.1038/ki.2010.25
van der Putten K, et al.: Nat Clin Pract Nephrol. 2008, 4: 47-57. 10.1038/ncpneph0655
Simon F, et al.: Shock. 2011,36(Suppl 1):S24.
Thim T: Dan Med Bull. 2010, 57: B4161.
Author information
Authors and Affiliations
Rights and permissions
This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
McCook, O., Matějková, S., Matallo, J. et al. Reduced EPO receptor expression may contribute to limited pleiotropic effects of EPO during critical illness. Crit Care 16 (Suppl 1), P440 (2012). https://doi.org/10.1186/cc11047
Published:
DOI: https://doi.org/10.1186/cc11047