Hyperphosphatemia and karbamylation proteins — risk factors for cardiovascular disease.

Prof. II Topchii. GI «National Institute of Therapy named after L.T. Malaya Academy of Medical Sciences of Ukraine» , Kharkiv.

The paper presents the data of their research and presented the latest information on new, non-traditional risk factors for cardiovascular events in patients with chronic kidney disease. It is shown that the content of FGF23 (one of the new risk factors for cardiovascular complications) in patients with diabetic nephropathy directly adjusts the level of hyperphosphatemia and renal functional reserve decrease — with development karbamylation proteins.

Key Words: hyperphosphatemia, fibroblast growth factor 23, karbamylation proteins, cardiovascular diseases.

Topchii II. [Hyperphosphatemia and karbamylation proteins — risk factors for cardiovascular disease]. Shidnoevr. z. vnutr. simejnoi med. 2017;1:39-43. Russian.


1. Topchii II. [Changes of the morphogenetic proteins FGF23 and Klotho increase risk of cardiovascular events].Shidnoevr.z. vnutr. simejnoi med. 2016;2:28-33. Russian.
2. Topchii II, Kirienko AN, Shcheniavskaia EN, Efimova NV, Abolmasov AN. Pokazateli narushenie tselostnosti endoteliia pri ostrom koronarnom sindrome u bol’nykh khronicheskoi bolezn’iu pochek. Ostrye i neotlozhnye sostoianiia v praktike vracha. 2015;1:23-28. Russian.
3. American Diabetes Association. Standards of medical care in diabetes-2014.Diabetes Care. 2014 Jan;37 Suppl 1:S14-80. doi: 10.2337/dc14-S014. PubMed PMID: 24357209.
4. Ärnlöv J, Carlsson AC, Sundström J, Ingelsson E, Larsson A, Lind L, Larsson TE. Higher fibroblast growth factor-23 increases the risk of all-cause and cardiovascular mortality in the community. Kidney Int. 2013 Jan;83(1):160-6. doi: 10.1038/ki.2012.327. PubMed PMID: 22951890.
5. Berg AH, Drechsler C, Wenger J, Buccafusca R, Hod T, Kalim S, Ramma W, Parikh SM, Steen H, Friedman DJ, Danziger J, Wanner C, Thadhani R, Karumanchi SA. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci Transl Med. 2013 Mar 6;5(175):175ra29. doi: 10.1126/scitranslmed.3005218. PubMed PMID: 23467560; PubMed Central PMCID: PMC3697767.
6. D’Apolito M. Urea-induced ROS cause endothelial dysfunction in chronic renal failure. Atherosclerosis. 2015 Apr;239(2):393-400. doi: 10.1016/j.atherosclerosis.2015.01.034.
7. Drechsler C. Kalim S, Wenger J, Suntharalingam P. Protein carbamylation is associated with heart failure and mortality in diabetic patients with end-stage renal disease. Kidney Int. 2015 Jun;87(6): 1201–1208. doi:10.1038/ki.2014.429.
8. Duranton F, Depner TA, Argilés À. The saga of two centuries of urea: Nontoxic toxin or vice versa? Semin Nephrol. 2014 Mar;34(2):87-96. doi: 10.1016/j.semnephrol.2014.02.002.
9. El-Gamal D, Rao SP, Holzer M, Hallström S, Haybaeck J, Gauster M, Wadsack C, Kozina A, Frank S, Schicho R, Schuligoi R, Heinemann A, Marsche G. The urea decomposition product cyanate promotes endothelial dysfunction. Kidney Int.2014 Nov;86(5):923-931. doi: 10.1038/ki.2014.218.
10. Gallieni M, Pedone M. Left ventricular hypertrophy and serum phosphate in peritoneal dialysis patients. Kidney Int. 2013;84: 850.DOI: http://dx.doi.org/10.1038/ki.2013.259.
11. Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, Li J, Shehadeh LA, Hare JM, David V, Martin A, Fornoni A, Di Marco GS, Kentrup D, Reuter S, Mayer AB, Pavenstädt H, Stypmann J, Kuhn C, Hille S, Frey N, Leifheit-Nestler M, Richter B, Haffner D, Abraham R, Bange J, Sperl B, Ullrich A, Brand M, Wolf M, Faul C. Activation of cardiac fibroblast growth factor receptor 4 causes left ventricular hypertrophy. Cell Metab. 2015; V.22:1020-1032. doi: 10.1016/j.cmet.2015.09.002.
12. Gravesen E, Mace ML, Hofman-Bang J, Olgaard K, Lewin E. Circulating FGF23 levels in response to acute changes in plasma Ca(2+). Calcif Tissue Int.2014.V. 95:46-53. doi: 10.1186/s12882-015-0019-3.
13. International Diabetes Federation. IDF Diabetes Atlas.7th Edition. 2015.78.doi: 10.2196/jmir.5567.
14. Jimbo R, Kawakami-Mori F, Mu S, Hirohama D, Majtan B, Shimizu Y, Yatomi Y, Fukumoto S, Fujita T, Shimosawa T. Fibroblast growth factor 23 accelerates phosphate-induced vascular calcification in the absence of Klotho deficiency. Kidney Int. 2014.V. 85:1103-1111.doi: 10.1038/ki.2013.332.
15. Kalim S, Karumanchi SA, Thadhani RI, Berg AH. Protein carbamylation in kidney disease: pathogenesis and clinical implications. Am J Kidney Dis. 2014 Nov;64(5):793-803. doi: 10.1053/j.ajkd.2014.04.034.
16. Kalim S, Ortiz G, Trottier CA, Deferio JJ, Karumanchi SA, Thadhani RI, Berg AH. The effects of parenteral amino acid therapy on protein carbamylation in maintenance hemodialysis patients.J Ren Nutr. 2015 March 5. doi:10.1053/j.jrn.2015.01.019.
17. Lindberg K, Amin R, Moe OW, Hu MC, Erben RG, Wernerson AÖ, Lanske B, Olauson H, Larsson TE. The kidney is the principal organ mediating klotho effects. J Am Soc Nephrol. 2014 Oct;25(10):2169-2175. doi: 10.1681/ASN.2013111209.
18. Liyanage T, Ninomiya T, Jha V, Neal B, Patrice HM, Okpechi I, Zhao MH, Lv J, Garg AX, Knight J, Rodgers A, Gallagher M, Kotwal S, Cass A, Perkovic V. Worldwide access to treatment for end-stage kidney disease: a systematic review. Lancet. 2015 May16;385(9981):1975-1982. doi: 10.1016/S0140-6736(14)61601-9.
19. Mendoza JM, Isakova T, Cai X, Bayes LY, Faul C, Scialla J. Inflammation and elevated levels of fibroblast growth factor 23 are independent risk factors for death in chronic kidney disease. Kidney Int. 2017 Mar;91(3):711-719. doi: 10.1016/j.kint.2016.10.021.
20. Mills KT, Xu Y, Zhang W, Bundy JD, Chen CS, Kelly TN, Chen J, He J. A systematic analysis of worldwide population-based data on the global burden of chronic kidney disease in 2010. Kidney Int. 2015 Nov;88(5):950-7. doi: 10.1038/ki.2015.230.
21. Pietrement C, Gorisse L, Gillery J, Gillery P. Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD. PLoS One [online]. 2013;8(12): e82506. doi: 10.1371/journal.pone.0082506.
22. Rebholz CM, Grams ME, Coresh J, Selvin E, Inker LA, Levey AS, Kimmel PL, Vasan RS, Eckfeldt JH, Feldman HI, Hsu C, Lutsey PL. Serum fibroblast growth factor-23 is associated with incident kidney disease. J Am Soc Nephrol. 2015 Jan;26(1):192-200. doi: 10.1681/ASN.2014060621.
23. Ruiz S, Pergola PE, Zager RA, Vaziri ND. Targeting the transcription factor Nrf2 to ameliorate oxidative stress and inflammation in chronic kidney disease. Kidney Int. 2013 Jun;83(6): 1029–1041. doi: 10.1038/ki.2012.439.
24. Tang WH, Shrestha K, Wang Z, Borowski AG, Troughton RW, Klein AL, Hazen SL. Protein carbamylation in chronic systolic heart failure: relationship with renal impairment and adverse long-term outcomes. J Card Fail. 2013 Apr;19(4): 219–224. doi: 10.1016/j.cardfail.2013.02.001.
25. Taniguchi M, Fukagawa M, Fujii N, Hamano T, Shoji T, Yokoyama K, Nakai S, Shigematsu T, Iseki K, Tsubakihara Y; Committee of Renal Data Registry of the Japanese Society for Dialysis Therapy. Serum phosphate and calcium should be primarily and consistently controlled in prevalent hemodialysis patients. Ther Apher Dial. 2013 Apr;17(2):221-228. doi: 10.1111/1744-9987.12030.
26. Trivin C, Metzger M, Haymann JP, Boffa JJ, Flamant M, Vrtovsnik F, Houillier P, Stengel B, Thervet E; NephroTest Study Group. Glycated hemoglobin level and mortality in a nondiabetic population with CKD. Clin J Am SocNephrol. 2015 Jun 5;10(6):914–916. doi: 10.2215/CJN.04200415.
27. Yamada S, Tokumoto M, Tatsumoto N, Taniguchi M, Noguchi H, Nakano T, Masutani K, Ooboshi H, Tsuruya K, Kitazono T. Phosphate overload directly induces systemic inflammation and malnutrition as well as vascular calcification in uremia. Am J Physiol Renal Physiol. 2014 Jun 15;306(12):F1418-1428. doi: 10.1152/ajprenal.00633.2013.
28. Understanding Needs in Low and Middle Income Countries. Implementation Strategies Conference. Bangkok, Thailand. June 18-21. 2015;8: 10.3402/gha.v8.27368.doi: 10.3402/gha.v8.27368.
29. Verbrugge FH, Wilson WH, Hazen TL.Protein carbamylation and cardiovascular disease. Kidney Int. 2015;V.88:474-478.
30. Wheeler DC, Kasiske BL. Statins for hemodialysis patients with diabetes? Long-term follow-up endorses the original conclusions of the 4D Study. Kidney Int. 2016 Jun;89(6):1189-1191. doi: 10.1016/j.kint.2016.02.045.
31. Wyatt C M, Drüeke TB. Fibroblast growth factor receptor 4:the missing link between chronic kidney disease and FGF23-induced left ventricular hypertrophy. Kidney Int. 2016 Jan;89(1):7-9. doi: 10.1016/j.kint.2015.11.012.