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Post-translational modifications in kidney diseases and associated cardiovascular risk

Nature Reviews Nephrology (2024)Cite this article

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Abstract

Patients with chronic kidney disease (CKD) are at an increased cardiovascular risk compared with the general population, which is driven, at least in part, by mechanisms that are uniquely associated with kidney disease. In CKD, increased levels of oxidative stress and uraemic retention solutes, including urea and advanced glycation end products, enhance non-enzymatic post-translational modification events, such as protein oxidation, glycation, carbamylation and guanidinylation. Alterations in enzymatic post-translational modifications such as glycosylation, ubiquitination, acetylation and methylation are also detected in CKD. Post-translational modifications can alter the structure and function of proteins and lipoprotein particles, thereby affecting cellular processes. In CKD, evidence suggests that post-translationally modified proteins can contribute to inflammation, oxidative stress and fibrosis, and induce vascular damage or prothrombotic effects, which might contribute to CKD progression and/or increase cardiovascular risk in patients with CKD. Consequently, post-translational protein modifications prevalent in CKD might be useful as diagnostic biomarkers and indicators of disease activity that could be used to guide and evaluate therapeutic interventions, in addition to providing potential novel therapeutic targets.

Key points

  • Non-enzymatic post-translational modifications, including oxidation, carbamylation, guanidinylation and glycation, can be enhanced in chronic kidney disease (CKD) owing to increases in oxidative stress, inflammation and retention of uraemic solutes.

  • These alterations in post-translational protein modifications might contribute to the pathophysiology of CKD.

  • Mechanistically, protein modifications in CKD can contribute to inflammation, oxidative stress, fibrosis, vascular damage and/or prothrombotic effects, thereby accelerating CKD progression and increasing cardiovascular risk.

  • Specific alterations in enzymatic post-translational modifications, such as glycosylation, ubiquitination, acetylation and methylation, might also contribute to the pathophysiology of CKD and cardiovascular disease.

  • Post-translational modifications are highly valuable diagnostic and prognostic disease biomarkers and represent interesting potential therapeutic targets, although additional research focus and investment will be required to translate this potential.

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Fig. 1: Impact of post-translational modifications on CKD and cardiovascular risk in CKD.
Fig. 2: Impact of non-enzymatic post-translational modifications on inflammation and oxidative stress in CKD.
Fig. 3: Impact of non-enzymatic and enzymatic post-translational modifications on vascular calcification in CKD.
Fig. 4: Impact of non-enzymatic and enzymatic post-translational modifications on kidney fibrosis in CKD.
Fig. 5: Impact of non-enzymatic and enzymatic post-translational modifications on thrombotic and bleeding risk in CKD.

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References

  1. Hill, N. R. et al. Global prevalence of chronic kidney disease — a systematic review and meta-analysis. PLoS One 11, e0158765 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  2. Himmelfarb, J., Vanholder, R., Mehrotra, R. & Tonelli, M. The current and future landscape of dialysis. Nat. Rev. Nephrol. 16, 573–585 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Matsushita, K. et al. Epidemiology and risk of cardiovascular disease in populations with chronic kidney disease. Nat. Rev. Nephrol. 18, 696–707 (2022).

    Article  PubMed  Google Scholar 

  4. Junho, C. V. C., Frisch, J., Soppert, J., Wollenhaupt, J. & Noels, H. Cardiomyopathy in chronic kidney disease: clinical features, biomarkers and the contribution of murine models in understanding pathophysiology. Clin. Kidney J. https://doi.org/10.1093/ckj/sfad085 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Jankowski, J., Floege, J., Fliser, D., Böhm, M. & Marx, N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 143, 1157–1172 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Noels, H. & Jankowski, J. Increased risk of cardiovascular complications in chronic kidney disease: introduction to a compendium. Circ. Res. 132, 899–901 (2023).

    Article  CAS  PubMed  Google Scholar 

  7. Cases Amenós, A., González-Juanatey, J. R., Conthe Gutiérrez, P., Matalí Gilarranz, A. & Garrido Costa, C. Prevalence of chronic kidney disease in patients with or at a high risk of cardiovascular disease. Rev. Esp. Cardiol. 63, 225–228 (2010).

    PubMed  Google Scholar 

  8. Wan, E. Y. F. et al. Burden of CKD and cardiovascular disease on life expectancy and health service utilization: a cohort study of Hong Kong Chinese hypertensive patients. J. Am. Soc. Nephrol. 30, 1991–1999 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zoccali, C. & Mallamaci, F. Innate immunity system in patients with cardiovascular and kidney disease. Circ. Res. 132, 915–932 (2023).

    Article  CAS  PubMed  Google Scholar 

  10. Ebert, T. et al. Inflammation and oxidative stress in chronic kidney disease and dialysis patients. Antioxid. Redox Signal. 35, 1426–1448 (2021).

    Article  CAS  PubMed  Google Scholar 

  11. Schreibing, F., Anslinger, T. M. & Kramann, R. Fibrosis in pathology of heart and kidney: from deep RNA-sequencing to novel molecular TARGets. Circ. Res. 132, 1013–1033 (2023).

    Article  CAS  PubMed  Google Scholar 

  12. Baaten, C., Vondenhoff, S. & Noels, H. Endothelial cell dysfunction and increased cardiovascular risk in patients with chronic kidney disease. Circ. Res. 132, 970–992 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hutcheson, J. D. & Goettsch, C. Cardiovascular calcification heterogeneity in chronic kidney disease. Circ. Res. 132, 993–1012 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baaten, C. et al. Platelet abnormalities in CKD and their implications for antiplatelet therapy. Clin. J. Am. Soc. Nephrol. 17, 155–170 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Thakur, M. et al. NETs-induced thrombosis impacts on cardiovascular and chronic kidney disease. Circ. Res. 132, 933–949 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ruiz-Ortega, M., Rayego-Mateos, S., Lamas, S., Ortiz, A. & Rodrigues-Diez, R. R. Targeting the progression of chronic kidney disease. Nat. Rev. Nephrol. 16, 269–288 (2020).

    Article  PubMed  Google Scholar 

  17. Yeung, C. K., Shen, D. D., Thummel, K. E. & Himmelfarb, J. Effects of chronic kidney disease and uremia on hepatic drug metabolism and transport. Kidney Int. 85, 522–528 (2014).

    Article  CAS  PubMed  Google Scholar 

  18. Verbrugge, F. H., Tang, W. H. & Hazen, S. L. Protein carbamylation and cardiovascular disease. Kidney Int. 88, 474–478 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Schunk, S. J. et al. Guanidinylated apolipoprotein C3 (ApoC3) associates with kidney and vascular injury. J. Am. Soc. Nephrol. 32, 3146–3160 (2021). This study identified guanidinylated ApoC3 and its association with declining kidney function and cardiovascular events in patients with CKD, and revealed that guanidinylated ApoC3 promoted kidney fibrosis and reduced injury-induced endothelial regeneration in animal models.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang, Z. et al. Protein carbamylation links inflammation, smoking, uremia and atherogenesis. Nat. Med. 13, 1176–1184 (2007). This report identified the occurrence of protein carbamylation at sites of inflammation and atherosclerotic lesions through MPO-catalyzed oxidation of thiocyanate, and revealed that levels of carbamylated protein lysine residues predict cardiovascular event risk in individuals with largely preserved kidney function.

    Article  CAS  PubMed  Google Scholar 

  21. Delporte, C. et al. Myeloperoxidase-catalyzed oxidation of cyanide to cyanate: a potential carbamylation route involved in the formation of atherosclerotic plaques? J. Biol. Chem. 293, 6374–6386 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Berg, A. H. et al. Carbamylation of serum albumin as a risk factor for mortality in patients with kidney failure. Sci. Transl. Med. 5, 175ra129 (2013).

    Article  Google Scholar 

  23. Kalim, S. et al. Protein carbamylation and the risk of ESKD in patients with CKD. J. Am. Soc. Nephrol. 34, 876–885 (2023).

    Article  PubMed  Google Scholar 

  24. Kalim, S. et al. Longitudinal changes in protein carbamylation and mortality risk after initiation of hemodialysis. Clin. J. Am. Soc. Nephrol. 11, 1809–1816 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Koeth, R. A. et al. Protein carbamylation predicts mortality in ESRD. J. Am. Soc. Nephrol. 24, 853–861 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Taes, Y. E. et al. Guanidino compounds after creatine supplementation in renal failure patients and their relation to inflammatory status. Nephrol. Dial. Transpl. 23, 1330–1335 (2008).

    Article  CAS  Google Scholar 

  27. Schuett, K. et al. Clot structure: a potent mortality risk factor in patients on hemodialysis. J. Am. Soc. Nephrol. 28, 1622–1630 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Speer, T. et al. Abnormal high-density lipoprotein induces endothelial dysfunction via activation of Toll-like receptor-2. Immunity 38, 754–768 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Zewinger, S. et al. Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease. Eur. Heart J. 38, 1597–1607 (2017). This work reported that the guanidine compound SDMA accumulated in HDL in patients with CKD, rendering HDL into a pro-inflammatory lipoprotein particle associated with increased mortality in CKD.

    Article  CAS  PubMed  Google Scholar 

  30. Sies, H. et al. Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat. Rev. Mol. Cell Biol. 23, 499–515 (2022).

    Article  CAS  PubMed  Google Scholar 

  31. Alhamdani, M. S., Al-Kassir, A. H., Jaleel, N. A., Hmood, A. M. & Ali, H. M. Elevated levels of alkanals, alkenals and 4-HO-alkenals in plasma of hemodialysis patients. Am. J. Nephrol. 26, 299–303 (2006).

    Article  CAS  PubMed  Google Scholar 

  32. Soulage, C. O. et al. Two toxic lipid aldehydes, 4-hydroxy-2-hexenal (4-HHE) and 4-hydroxy-2-nonenal (4-HNE), accumulate in patients with chronic kidney disease. Toxins 12, 567 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Miyata, T., Kurokawa, K. & van Ypersele de Strihou, C. Relevance of oxidative and carbonyl stress to long-term uremic complications. Kidney Int. Suppl. 76, S120–S125 (2000).

    Article  CAS  PubMed  Google Scholar 

  34. Mera, K. et al. Oxidation and carboxy methyl lysine-modification of albumin: possible involvement in the progression of oxidative stress in hemodialysis patients. Hypertens. Res. 28, 973–980 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Mitrogianni, Z., Barbouti, A., Galaris, D. & Siamopoulos, K. C. Oxidative modification of albumin in predialysis, hemodialysis, and peritoneal dialysis patients. Nephron Clin. Pract. 113, c234–c240 (2009).

    Article  CAS  PubMed  Google Scholar 

  36. Witko-Sarsat, V. et al. Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int. 49, 1304–1313 (1996).

    Article  CAS  PubMed  Google Scholar 

  37. Kaneda, H., Taguchi, J., Ogasawara, K., Aizawa, T. & Ohno, M. Increased level of advanced oxidation protein products in patients with coronary artery disease. Atherosclerosis 162, 221–225 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Cao, W., Hou, F. F. & Nie, J. AOPPs and the progression of kidney disease. Kidney Int. Suppl. 4, 102–106 (2014).

    Article  CAS  Google Scholar 

  39. Valli, A. et al. Overestimation of advanced oxidation protein products in uremic plasma due to presence of triglycerides and other endogenous factors. Clin. Chim. Acta 379, 87–94 (2007).

    Article  CAS  PubMed  Google Scholar 

  40. Zhou, C. et al. Association between serum advanced oxidation protein products and mortality risk in maintenance hemodialysis patients. J. Transl. Med. 19, 284 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature 414, 813–820 (2001).

    Article  CAS  PubMed  Google Scholar 

  42. Dozio, E. et al. Accelerated AGEing: the impact of advanced glycation end products on the prognosis of chronic kidney disease. Antioxidants 12, 584 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Stinghen, A. E., Massy, Z. A., Vlassara, H., Striker, G. E. & Boullier, A. Uremic toxicity of advanced glycation end products in CKD. J. Am. Soc. Nephrol. 27, 354–370 (2016).

    Article  CAS  PubMed  Google Scholar 

  44. Agalou, S., Ahmed, N., Babaei-Jadidi, R., Dawnay, A. & Thornalley, P. J. Profound mishandling of protein glycation degradation products in uremia and dialysis. J. Am. Soc. Nephrol. 16, 1471–1485 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Rabbani, N., Sebekova, K., Sebekova, K. Jr., Heidland, A. & Thornalley, P. J. Accumulation of free adduct glycation, oxidation, and nitration products follows acute loss of renal function. Kidney Int. 72, 1113–1121 (2007).

    Article  CAS  PubMed  Google Scholar 

  46. Uchiki, T. et al. Glycation-altered proteolysis as a pathobiologic mechanism that links dietary glycemic index, aging, and age-related disease (in nondiabetics). Aging Cell 11, 1–13 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Mallipattu, S. K., He, J. C. & Uribarri, J. Role of advanced glycation endproducts and potential therapeutic interventions in dialysis patients. Semin. Dial. 25, 529–538 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ramazi, S. & Zahiri, J. Posttranslational modifications in proteins: resources, tools and prediction methods. Database 2021, baab012 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Cao, Y. et al. An overview of the posttranslational modifications and related molecular mechanisms in diabetic nephropathy. Front. Cell Dev. Biol. 9, 630401 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Wang, X., Liu, T., Huang, Y., Dai, Y. & Lin, H. Regulation of transforming growth factor-β signalling by SUMOylation and its role in fibrosis. Open. Biol. 11, 210043 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Aranda-Rivera, A. K., Cruz-Gregorio, A., Aparicio-Trejo, O. E. & Pedraza-Chaverri, J. Mitochondrial redox signaling and oxidative stress in kidney diseases. Biomolecules 11, 1144 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. He, W. J. et al. Association of mitochondrial DNA copy number with risk of progression of kidney disease. Clin. J. Am. Soc. Nephrol. 17, 966–975 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fazzini, F. et al. Mitochondrial DNA copy number is associated with mortality and infections in a large cohort of patients with chronic kidney disease. Kidney Int. 96, 480–488 (2019).

    Article  CAS  PubMed  Google Scholar 

  54. Afshinnia, F. et al. Myeloperoxidase levels and its product 3-chlorotyrosine predict chronic kidney disease severity and associated coronary artery disease. Am. J. Nephrol. 46, 73–81 (2017).

    Article  CAS  PubMed  Google Scholar 

  55. Vanholder, R., Pletinck, A., Schepers, E. & Glorieux, G. Biochemical and clinical impact of organic uremic retention solutes: a comprehensive update. Toxins 10, 33 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Harlacher, E., Wollenhaupt, J., Baaten, C. & Noels, H. Impact of uremic toxins on endothelial dysfunction in chronic kidney disease: a systematic review. Int. J. Mol. Sci. 23, 531 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Mera, K. et al. The structure and function of oxidized albumin in hemodialysis patients: its role in elevated oxidative stress via neutrophil burst. Biochem. Biophys. Res. Commun. 334, 1322–1328 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Rong, G. et al. Advanced oxidation protein products induce apoptosis in podocytes through induction of endoplasmic reticulum stress. J. Physiol. Biochem. 71, 455–470 (2015).

    Article  CAS  PubMed  Google Scholar 

  59. Iwao, Y. et al. CD36 is one of important receptors promoting renal tubular injury by advanced oxidation protein products. Am. J. Physiol. Renal Physiol. 295, F1871–F1880 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Li, H. Y. et al. Advanced oxidation protein products accelerate renal fibrosis in a remnant kidney model. J. Am. Soc. Nephrol. 18, 528–538 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Marsche, G. et al. Hypochlorite-modified albumin colocalizes with RAGE in the artery wall and promotes MCP-1 expression via the RAGE-Erk1/2 MAP-kinase pathway. FASEB J. 21, 1145–1152 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Chen, Y. et al. p53 SUMOylation mediates AOPP-induced endothelial senescence and apoptosis evasion. Front. Cardiovasc. Med. 8, 795747 (2021).

    Article  CAS  PubMed  Google Scholar 

  63. Liu, S. X. et al. Advanced oxidation protein products accelerate atherosclerosis through promoting oxidative stress and inflammation. Arterioscler. Thromb. Vasc. Biol. 26, 1156–1162 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Feng, W. et al. Advanced oxidation protein products aggravate cardiac remodeling via cardiomyocyte apoptosis in chronic kidney disease. Am. J. Physiol. Heart Circ. Physiol. 314, H475–H483 (2018).

    Article  PubMed  Google Scholar 

  65. Delporte, C. et al. Impact of myeloperoxidase-LDL interactions on enzyme activity and subsequent posttranslational oxidative modifications of apoB-100. J. Lipid Res. 55, 747–757 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Drożdż, D. et al. Oxidative stress biomarkers and left ventricular hypertrophy in children with chronic kidney disease. Oxid. Med. Cell Longev. 2016, 7520231 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Le Master, E. et al. Proatherogenic flow increases endothelial stiffness via enhanced CD36-mediated uptake of oxidized low-density lipoproteins. Arterioscler. Thromb. Vasc. Biol. 38, 64–75 (2018).

    Article  PubMed  Google Scholar 

  68. Soppert, J., Lehrke, M., Marx, N., Jankowski, J. & Noels, H. Lipoproteins and lipids in cardiovascular disease: from mechanistic insights to therapeutic targeting. Adv. Drug Deliv. Rev. 159, 4–33 (2020).

    Article  CAS  PubMed  Google Scholar 

  69. Hou, J. S. et al. Serum malondialdehyde-modified low-density lipoprotein is a risk factor for central arterial stiffness in maintenance hemodialysis patients. Nutrients 12, 2160 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Noels, H., Lehrke, M., Vanholder, R. & Jankowski, J. Lipoproteins and fatty acids in chronic kidney disease: molecular and metabolic alterations. Nat. Rev. Nephrol. 17, 528–542 (2021).

    Article  CAS  PubMed  Google Scholar 

  71. Moradi, H., Pahl, M. V., Elahimehr, R. & Vaziri, N. D. Impaired antioxidant activity of high-density lipoprotein in chronic kidney disease. Transl. Res. 153, 77–85 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Gao, X. et al. Oxidized high-density lipoprotein impairs the function of human renal proximal tubule epithelial cells through CD36. Int. J. Mol. Med. 34, 564–572 (2014).

    Article  CAS  PubMed  Google Scholar 

  73. Yao, S. et al. Oxidized high density lipoprotein induces macrophage apoptosis via Toll-like receptor 4-dependent CHOP pathway. J. Lipid Res. 58, 164–177 (2017).

    Article  CAS  PubMed  Google Scholar 

  74. Pérez, L. et al. OxHDL controls LOX-1 expression and plasma membrane localization through a mechanism dependent on NOX/ROS/NF-κB pathway on endothelial cells. Lab. Invest. 99, 421–437 (2019).

    Article  PubMed  Google Scholar 

  75. Honda, H. et al. Oxidized high-density lipoprotein as a risk factor for cardiovascular events in prevalent hemodialysis patients. Atherosclerosis 220, 493–501 (2012).

    Article  CAS  PubMed  Google Scholar 

  76. Marsche, G. et al. Plasma-advanced oxidation protein products are potent high-density lipoprotein receptor antagonists in vivo. Circ. Res. 104, 750–757 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Van Eck, M. et al. Increased oxidative stress in scavenger receptor BI knockout mice with dysfunctional HDL. Arterioscler. Thromb. Vasc. Biol. 27, 2413–2419 (2007).

    Article  PubMed  Google Scholar 

  78. Ok, E., Basnakian, A. G., Apostolov, E. O., Barri, Y. M. & Shah, S. V. Carbamylated low-density lipoprotein induces death of endothelial cells: a link to atherosclerosis in patients with kidney disease. Kidney Int. 68, 173–178 (2005).

    Article  CAS  PubMed  Google Scholar 

  79. Speer, T. et al. Carbamylated low-density lipoprotein induces endothelial dysfunction. Eur. Heart J. 35, 3021–3032 (2014).

    Article  CAS  PubMed  Google Scholar 

  80. Apostolov, E. O., Ray, D., Savenka, A. V., Shah, S. V. & Basnakian, A. G. Chronic uremia stimulates LDL carbamylation and atherosclerosis. J. Am. Soc. Nephrol. 21, 1852–1857 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hörkkö, S., Huttunen, K., Kervinen, K. & Kesäniemi, Y. A. Decreased clearance of uraemic and mildly carbamylated low-density lipoprotein. Eur. J. Clin. Invest. 24, 105–113 (1994).

    Article  PubMed  Google Scholar 

  82. Sun, J. T. et al. Increased carbamylation level of HDL in end-stage renal disease: carbamylated-HDL attenuated endothelial cell function. Am. J. Physiol. Renal Physiol. 310, F511–F517 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Chang, C. T. et al. PON-1 carbamylation is enhanced in HDL of uremia patients. J. Food Drug Anal. 27, 542–550 (2019).

    Article  CAS  PubMed  Google Scholar 

  84. Tan, K. C. B. et al. Carbamylated lipoproteins and progression of diabetic kidney disease. Clin. J. Am. Soc. Nephrol. 15, 359–366 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Holzer, M. et al. Protein carbamylation renders high-density lipoprotein dysfunctional. Antioxid. Redox Signal. 14, 2337–2346 (2011).

    Article  CAS  PubMed  Google Scholar 

  86. Zewinger, S. et al. Serum amyloid A: high-density lipoproteins interaction and cardiovascular risk. Eur. Heart J. 36, 3007–3016 (2015).

    CAS  PubMed  Google Scholar 

  87. Schuchardt, M. et al. Dysfunctional high-density lipoprotein activates Toll-like receptors via serum amyloid A in vascular smooth muscle cells. Sci. Rep. 9, 3421 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Holzer, M. et al. Uremia alters HDL composition and function. J. Am. Soc. Nephrol. 22, 1631–1641 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Shao, B. et al. A cluster of proteins implicated in kidney disease is increased in high-density lipoprotein isolated from hemodialysis subjects. J. Proteome Res. 14, 2792–2806 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Weichhart, T. et al. Serum amyloid A in uremic HDL promotes inflammation. J. Am. Soc. Nephrol. 23, 934–947 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Artl, A., Marsche, G., Lestavel, S., Sattler, W. & Malle, E. Role of serum amyloid A during metabolism of acute-phase HDL by macrophages. Arterioscler. Thromb. Vasc. Biol. 20, 763–772 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Jaisson, S. et al. Carbamylated albumin is a potent inhibitor of polymorphonuclear neutrophil respiratory burst. FEBS Lett. 581, 1509–1513 (2007).

    Article  CAS  PubMed  Google Scholar 

  93. Jaisson, S. et al. Impact of carbamylation on type I collagen conformational structure and its ability to activate human polymorphonuclear neutrophils. Chem. Biol. 13, 149–159 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Rueth, M. et al. Guanidinylations of albumin decreased binding capacity of hydrophobic metabolites. Acta Physiol. 215, 13–23 (2015).

    Article  CAS  Google Scholar 

  95. Cohen, M. P., Shea, E., Chen, S. & Shearman, C. W. Glycated albumin increases oxidative stress, activates NF-κ B and extracellular signal-regulated kinase (ERK), and stimulates ERK-dependent transforming growth factor-β1 production in macrophage RAW cells. J. Lab. Clin. Med. 141, 242–249 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Higai, K., Satake, M., Nishioka, H., Azuma, Y. & Matsumoto, K. Glycated human serum albumin enhances macrophage inflammatory protein-1β mRNA expression through protein kinase C-δ and NADPH oxidase in macrophage-like differentiated U937 cells. Biochim. Biophys. Acta 1780, 307–314 (2008).

    Article  CAS  PubMed  Google Scholar 

  97. Rubenstein, D. A., Maria, Z. & Yin, W. Glycated albumin modulates endothelial cell thrombogenic and inflammatory responses. J. Diabetes Sci. Technol. 5, 703–713 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Bucala, R. et al. Modification of low density lipoprotein by advanced glycation end products contributes to the dyslipidemia of diabetes and renal insufficiency. Proc. Natl Acad. Sci. USA 91, 9441–9445 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Hodgkinson, C. P., Laxton, R. C., Patel, K. & Ye, S. Advanced glycation end-product of low density lipoprotein activates the Toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 2275–2281 (2008).

    Article  CAS  PubMed  Google Scholar 

  100. Chen, C. et al. Damage of uremic myocardium by p-cresyl sulfate and the ameliorative effect of klotho by regulating SIRT6 ubiquitination. Toxicol. Lett. 367, 19–31 (2022).

    Article  CAS  PubMed  Google Scholar 

  101. Winnik, S., Auwerx, J., Sinclair, D. A. & Matter, C. M. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur. Heart J. 36, 3404–3412 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wang, Y. J., Paneni, F., Stein, S. & Matter, C. M. Modulating sirtuin biology and nicotinamide adenine diphosphate metabolism in cardiovascular disease — from bench to bedside. Front. Physiol. 12, 755060 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Grootaert, M. O. J. & Bennett, M. R. Sirtuins in atherosclerosis: guardians of healthspan and therapeutic targets. Nat. Rev. Cardiol. 19, 668–683 (2022).

    Article  CAS  PubMed  Google Scholar 

  104. London, G. M. et al. Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol. Dial. Transpl. 18, 1731–1740 (2003).

    Article  Google Scholar 

  105. Holmar, J. et al. Uremic toxins affecting cardiovascular calcification: a systematic review. Cells 9, 2428 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Sun, J. T. et al. Oxidized HDL, as a novel biomarker for calcific aortic valve disease, promotes the calcification of aortic valve interstitial cells. J. Cardiovasc. Transl. Res. 12, 560–568 (2019).

    Article  CAS  PubMed  Google Scholar 

  107. Tanikawa, T., Okada, Y., Tanikawa, R. & Tanaka, Y. Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J. Vasc. Res. 46, 572–580 (2009).

    Article  CAS  PubMed  Google Scholar 

  108. Koike, S. et al. Advanced glycation end-products induce apoptosis of vascular smooth muscle cells: a mechanism for vascular calcification. Int. J. Mol. Sci. 17, 1567 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Mori, D. et al. Protein carbamylation exacerbates vascular calcification. Kidney Int. 94, 72–90 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. Jankowski, V. et al. Carbamylated sortilin associates with cardiovascular calcification in patients with chronic kidney disease. Kidney Int. 101, 574–584 (2022). This study reported that carbamylation of sortilin in patients with CKD was associated with cardiovascular calcification and revealed that, mechanistically, sortilin carbamylation enhanced osteogenic differentiation and calcification of vascular smooth muscle cells, which was further accelerated by sortilin binding to IL-6.

    Article  CAS  PubMed  Google Scholar 

  111. Alesutan, I. et al. Circulating uromodulin inhibits vascular calcification by interfering with pro-inflammatory cytokine signalling. Cardiovasc. Res. 117, 930–941 (2021).

    Article  CAS  PubMed  Google Scholar 

  112. Schurgers, L. J. et al. Post-translational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification. J. Thromb. Haemost. 5, 2503–2511 (2007).

    Article  CAS  PubMed  Google Scholar 

  113. Schurgers, L. J. et al. The circulating inactive form of matrix Gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin. J. Am. Soc. Nephrol. 5, 568–575 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Schlieper, G. et al. Circulating nonphosphorylated carboxylated matrix Gla protein predicts survival in ESRD. J. Am. Soc. Nephrol. 22, 387–395 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Roumeliotis, S., Dounousi, E., Eleftheriadis, T. & Liakopoulos, V. Association of the inactive circulating matrix Gla protein with vitamin K intake, calcification, mortality, and cardiovascular disease: a review. Int. J. Mol. Sci. 20, 628 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhang, Y. et al. The ameliorative effect of terpinen-4-ol on ER stress-induced vascular calcification depends on SIRT1-mediated regulation of PERK acetylation. Pharmacol. Res. 170, 105629 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Yang, L. et al. Unspliced XBP1 counteracts β-catenin to inhibit vascular calcification. Circ. Res. 130, 213–229 (2022).

    Article  CAS  PubMed  Google Scholar 

  118. Carlisle, R. E. et al. TDAG51 induces renal interstitial fibrosis through modulation of TGF-β receptor 1 in chronic kidney disease. Cell Death Dis. 12, 921 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Ouyang, L. et al. Indoleamine 2,3-dioxygenase 1 deletion-mediated kynurenine insufficiency in vascular smooth muscle cells exacerbates arterial calcification. Circulation 145, 1784–1798 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Vanholder, R., Nigam, S. K., Burtey, S. & Glorieux, G. What if not all metabolites from the uremic toxin generating pathways are toxic? A hypothesis. Toxins 14, 221 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Wang, Y. et al. DUSP26 induces aortic valve calcification by antagonizing MDM2-mediated ubiquitination of DPP4 in human valvular interstitial cells. Eur. Heart J. 42, 2935–2951 (2021).

    Article  CAS  PubMed  Google Scholar 

  122. Choi, B. et al. Dipeptidyl peptidase-4 induces aortic valve calcification by inhibiting insulin-like growth factor-1 signaling in valvular interstitial cells. Circulation 135, 1935–1950 (2017).

    Article  CAS  PubMed  Google Scholar 

  123. Xu, T. H. et al. OGT-mediated KEAP1 glycosylation accelerates NRF2 degradation leading to high phosphate-induced vascular calcification in chronic kidney disease. Front. Physiol. 11, 1092 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  124. Jin, D. et al. NRF2-suppressed vascular calcification by regulating the antioxidant pathway in chronic kidney disease. FASEB J. 36, e22098 (2022).

    Article  CAS  PubMed  Google Scholar 

  125. Yimamu, Y. et al. 25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) induces ectopic calcification. J. Clin. Biochem. Nutr. 71, 103–111 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Torremadé, N. et al. Vascular calcification induced by chronic kidney disease is mediated by an increase of 1α-hydroxylase expression in vascular smooth muscle cells. J. Bone Min. Res. 31, 1865–1876 (2016).

    Article  Google Scholar 

  127. Masbuchin, A. N., Rohman, M. S. & Liu, P. Y. Role of glycosylation in vascular calcification. Int. J. Mol. Sci. 22, 9829 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Grande, M. T. et al. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat. Med. 21, 989–997 (2015).

    Article  CAS  PubMed  Google Scholar 

  129. Gorisse, L. et al. Protein carbamylation is a hallmark of aging. Proc. Natl Acad. Sci. USA 113, 1191–1196 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Desmons, A. et al. Proteasome-dependent degradation of intracellular carbamylated proteins. Aging 11, 3624–3638 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Pietrement, C., Gorisse, L., Jaisson, S. & Gillery, P. Chronic increase of urea leads to carbamylated proteins accumulation in tissues in a mouse model of CKD. PLoS One 8, e82506 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Jaisson, S. et al. Carbamylation differentially alters type I collagen sensitivity to various collagenases. Matrix Biol. 26, 190–196 (2007).

    Article  CAS  PubMed  Google Scholar 

  133. Garnotel, R., Sabbah, N., Jaisson, S. & Gillery, P. Enhanced activation of and increased production of matrix metalloproteinase-9 by human blood monocytes upon adhering to carbamylated collagen. FEBS Lett. 563, 13–16 (2004).

    Article  CAS  PubMed  Google Scholar 

  134. Gilcrease, M. Z. & Hoover, R. L. Human monocyte interactions with non-enzymatically glycated collagen. Diabetologia 35, 160–164 (1992).

    Article  CAS  PubMed  Google Scholar 

  135. Wolffenbuttel, B. H. et al. Breakers of advanced glycation end products restore large artery properties in experimental diabetes. Proc. Natl Acad. Sci. USA 95, 4630–4634 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Sell, D. R. & Monnier, V. M. Molecular basis of arterial stiffening: role of glycation — a mini-review. Gerontology 58, 227–237 (2012).

    Article  CAS  PubMed  Google Scholar 

  137. Ziyadeh, F. N., Han, D. C., Cohen, J. A., Guo, J. & Cohen, M. P. Glycated albumin stimulates fibronectin gene expression in glomerular mesangial cells: involvement of the transforming growth factor-β system. Kidney Int. 53, 631–638 (1998).

    Article  CAS  PubMed  Google Scholar 

  138. Chen, S., Cohen, M. P., Lautenslager, G. T., Shearman, C. W. & Ziyadeh, F. N. Glycated albumin stimulates TGF-β1 production and protein kinase C activity in glomerular endothelial cells. Kidney Int. 59, 673–681 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Cohen, M. P. et al. Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-β1. Kidney Int. 61, 2025–2032 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Cohen, M. P. et al. Inhibiting albumin glycation ameliorates diabetic nephropathy in the db/db mouse. Exp. Nephrol. 8, 135–143 (2000).

    Article  CAS  PubMed  Google Scholar 

  141. Zhu, Q. et al. HUWE1 promotes EGFR ubiquitination and degradation to protect against renal tubulointerstitial fibrosis. FASEB J. 34, 4591–4601 (2020).

    Article  CAS  PubMed  Google Scholar 

  142. Saritas, T. et al. Disruption of CUL3-mediated ubiquitination causes proximal tubule injury and kidney fibrosis. Sci. Rep. 9, 4596 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Li, Y. et al. PTEN-induced partial epithelial-mesenchymal transition drives diabetic kidney disease. J. Clin. Invest. 129, 1129–1151 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Hirschey, M. D. et al. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation. Nature 464, 121–125 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Kang, H. M. et al. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development. Nat. Med. 21, 37–46 (2015).

    Article  CAS  PubMed  Google Scholar 

  146. Zhang, Y. et al. Sirtuin 3 regulates mitochondrial protein acetylation and metabolism in tubular epithelial cells during renal fibrosis. Cell Death Dis. 12, 847 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lin, W. et al. Klotho restoration via acetylation of peroxisome proliferation-activated receptor γ reduces the progression of chronic kidney disease. Kidney Int. 92, 669–679 (2017).

    Article  CAS  PubMed  Google Scholar 

  148. Moreno, J. A. et al. The inflammatory cytokines TWEAK and TNFα reduce renal klotho expression through NFκB. J. Am. Soc. Nephrol. 22, 1315–1325 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Shen, F. & Zhuang, S. Histone acetylation and modifiers in renal fibrosis. Front. Pharmacol. 13, 760308 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Rauchman, M. & Griggs, D. Emerging strategies to disrupt the central TGF-β axis in kidney fibrosis. Transl. Res. 209, 90–104 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Xu, J., Zhou, L. & Liu, Y. Cellular senescence in kidney fibrosis: pathologic significance and therapeutic strategies. Front. Pharmacol. 11, 601325 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ebert, T., Tran, N., Schurgers, L., Stenvinkel, P. & Shiels, P. G. Ageing — oxidative stress, PTMs and disease. Mol. Asp. Med. 86, 101099 (2022).

    Article  CAS  Google Scholar 

  153. Shiels, P. G., McGuinness, D., Eriksson, M., Kooman, J. P. & Stenvinkel, P. The role of epigenetics in renal ageing. Nat. Rev. Nephrol. 13, 471–482 (2017).

    Article  CAS  PubMed  Google Scholar 

  154. Baaten, C. et al. Platelet function in CKD: a systematic review and meta-analysis. J. Am. Soc. Nephrol. 32, 1583–1598 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Pasterk, L. et al. Oxidized plasma albumin promotes platelet-endothelial crosstalk and endothelial tissue factor expression. Sci. Rep. 6, 22104 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Florens, N. et al. CKD increases carbonylation of HDL and is associated with impaired antiaggregant properties. J. Am. Soc. Nephrol. 31, 1462–1477 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Baralić, M. et al. Fibrinogen modification and fibrin formation in patients with an end-stage renal disease subjected to peritoneal dialysis. Biochemistry 85, 947–954 (2020).

    PubMed  Google Scholar 

  158. Rubenstein, D. A. & Yin, W. Glycated albumin modulates platelet susceptibility to flow induced activation and aggregation. Platelets 20, 206–215 (2009).

    Article  CAS  PubMed  Google Scholar 

  159. Soaita, I., Yin, W. & Rubenstein, D. A. Glycated albumin modifies platelet adhesion and aggregation responses. Platelets 28, 682–690 (2017).

    Article  CAS  PubMed  Google Scholar 

  160. Binder, V. et al. Impact of fibrinogen carbamylation on fibrin clot formation and stability. Thromb. Haemost. 117, 899–910 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  161. Binder, V. et al. Carbamylation of integrin αIIbβ3: the mechanistic link to platelet dysfunction in ESKD. J. Am. Soc. Nephrol. 33, 1841–1856 (2022). This study reported carbamylation of platelet integrin αIIbβ3 in patients with CKD, which interfered with integrin-mediated fibrinogen binding, platelet adhesion and aggregation, and might thus contribute to increased bleeding risk in CKD.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Lan, Q. et al. Renal klotho safeguards platelet lifespan in advanced chronic kidney disease through restraining Bcl-xL ubiquitination and degradation. J. Thromb. Haemost. 20, 2972–2987 (2022).

    Article  CAS  PubMed  Google Scholar 

  163. Chitalia, V. C. et al. Uremic serum and solutes increase post-vascular interventional thrombotic risk through altered stability of smooth muscle cell tissue factor. Circulation 127, 365–376 (2013).

    Article  CAS  PubMed  Google Scholar 

  164. Walker, J. A. et al. Indoleamine 2,3-dioxygenase-1, a novel therapeutic target for post-vascular injury thrombosis in CKD. J. Am. Soc. Nephrol. 32, 2834–2850 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Kannan, S., Krishnankutty, R. & Souchelnytskyi, S. Novel post-translational modifications in human serum albumin. Protein Pept. Lett. 29, 473–484 (2022).

    Article  CAS  PubMed  Google Scholar 

  166. Di Iorio, B. R. et al. Nutritional therapy reduces protein carbamylation through urea lowering in chronic kidney disease. Nephrol. Dial. Transplant. 33, 804–813 (2018).

    Article  PubMed  Google Scholar 

  167. Klahr, S. et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of diet in Renal Disease Study Group. N. Engl. J. Med. 330, 877–884 (1994).

    Article  CAS  PubMed  Google Scholar 

  168. Garneata, L., Stancu, A., Dragomir, D., Stefan, G. & Mircescu, G. Ketoanalogue-supplemented vegetarian very low-protein diet and CKD progression. J. Am. Soc. Nephrol. 27, 2164–2176 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Tang, M. et al. The impact of carbamylation and anemia on HbA1c’s association with renal outcomes in patients with diabetes and chronic kidney disease. Diabetes Care 46, 130–137 (2023).

    Article  CAS  PubMed  Google Scholar 

  170. Nicolas, C. et al. Carbamylation is a competitor of glycation for protein modification in vivo. Diabetes Metab. 44, 160–167 (2018).

    Article  CAS  PubMed  Google Scholar 

  171. Nicolas, C. et al. Carbamylation and glycation compete for collagen molecular aging in vivo. Sci. Rep. 9, 18291 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Weber, C. & Noels, H. Atherosclerosis: current pathogenesis and therapeutic options. Nat. Med. 17, 1410–1422 (2011).

    Article  CAS  PubMed  Google Scholar 

  173. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT05021835 (2024).

  174. Jong, J. A. W. et al. A ninhydrin-type urea sorbent for the development of a wearable artificial kidney. Macromol. Biosci. 20, e1900396 (2020).

    Article  PubMed  Google Scholar 

  175. Sternkopf, M. et al. A bifunctional adsorber particle for the removal of hydrophobic uremic toxins from whole blood of renal failure patients. Toxins 11, 389 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Kalim, S. et al. The effects of parenteral amino acid therapy on protein carbamylation in maintenance hemodialysis patients. J. Ren. Nutr. 25, 388–392 (2015). First proof-of concept investigation of amino acid therapy aimed at reducing protein carbamylation in patients receiving haemodialysis; demonstrated that scavenging reactive metabolites in the plasma of patients receiving haemodialysis can decrease albumin carbamylation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Delanghe, S., Delanghe, J. R., Speeckaert, R., Van Biesen, W. & Speeckaert, M. M. Mechanisms and consequences of carbamoylation. Nat. Rev. Nephrol. 13, 580–593 (2017).

    Article  CAS  PubMed  Google Scholar 

  178. Descamps-Latscha, B. et al. Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers. Kidney Int. 66, 1606–1612 (2004).

    Article  CAS  PubMed  Google Scholar 

  179. Descamps-Latscha, B. et al. Advanced oxidation protein products as risk factors for atherosclerotic cardiovascular events in nondiabetic predialysis patients. Am. J. Kidney Dis. 45, 39–47 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Zhou, Q. et al. Accumulation of circulating advanced oxidation protein products is an independent risk factor for ischaemic heart disease in maintenance haemodialysis patients. Nephrology 17, 642–649 (2012).

    Article  CAS  PubMed  Google Scholar 

  181. Zeng, L. et al. Myeloperoxidase-derived oxidants damage artery wall proteins in an animal model of chronic kidney disease-accelerated atherosclerosis. J. Biol. Chem. 293, 7238–7249 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by the German Research Foundation (DFG) SFB/TRR219 Project-ID 322900939 (C-04, C-09, M-05, S-03; to H.N., J.J., V.J. and S.J.S.); SFB 1382 Project-ID 403224013 (A-04 to H.N. and J.J.), the Else Kröner-Fresenius-Stiftung (Project 2020_EKEA.60 to H.N.), the German Centre for Cardiovascular Research (to H.N.) and the Interdisciplinary Center for Clinical Research (IZKF) within the Faculty of Medicine at the RWTH Aachen University (PTD 1-12 to H.N.). This work was further financially supported by INST 948/4S-1, the DFG Clinical Research Unit 5011 project number 445703531 (to V.J.) and IZKF ‘Multiorgan complexity in Friedreich Ataxia’ (V.J.). This article is also based on work from COST Action Permedik, CA21165, supported by COST (European Cooperation in Science and Technology). European Kidney Health Alliance is the recipient of support by the European Union in the context of the Annual Work Program 2022 on the prevention of non-communicable diseases of EU4Health, topic ID EU4H-2022-PJ02, project # 101101220 PREVENTCKD.

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Authors and Affiliations

  1. Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany

    Heidi Noels, Vera Jankowski & Joachim Jankowski

  2. Aachen-Maastricht Institute for Cardiorenal Disease (AMICARE), University Hospital RWTH Aachen, Aachen, Germany

    Heidi Noels, Vera Jankowski & Joachim Jankowski

  3. Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands

    Heidi Noels

  4. Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University, Homburg/Saar, Germany

    Stefan J. Schunk

  5. Nephrology Section, Department of Internal Medicine and Paediatrics, University Hospital, Ghent, Belgium

    Raymond Vanholder

  6. European Kidney Health Alliance (EKHA), Brussels, Belgium

    Raymond Vanholder

  7. Department of Medicine, Division of Nephrology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Sahir Kalim

  8. Department of Pathology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, Netherlands

    Joachim Jankowski

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Contributions

H.N., R.V. and S.K. researched data for the article. H.N., V.J., S.J.S., R.V. and S.K. made substantial contributions to discussions of the content. J.J. and H.N. wrote the article and all authors reviewed or edited the manuscript before submission.

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Correspondence to Heidi Noels or Joachim Jankowski.

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Competing interests

H.N. and J.J. are founding shareholders of AMICARE Development GmbH. R.V. is adviser to AstraZeneca, Glaxo Smith Kline, Fresenius Kabi, Novartis, Kibow, Baxter, Nipro, Fresenius Medical Care and Nextkidney. The other authors declare no competing interests.

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Glossary

Carboxylation

Reaction with carbon dioxide resulting in the generation of carboxylic acid (−COOH).

Epithelial-to-mesenchymal transition

(EMT). Phenotypic transition of epithelial cells to a mesenchymal cellular phenotype. ‘Partial EMT’ has been used to refer to a phenotypic transition of epithelial cells with reduced expression of epithelial cell markers and acquisition of mesenchymal cell markers, but without invasive phenotype and without direct contribution to interstitial fibrosis128.

Mitochondrial dysfunction

Malfunctioning of mitochondria with increased mitochondrial membrane permeability, cytochrome c release, excessive mitochondrial ROS accumulation and reduced mitochondrial ATP production, ultimately triggering apoptosis and cell death.

Mitochondrial fatty acid metabolism

Mitochondrial fatty acid β-oxidation (FAO) resulting in fatty acid degradation and the generation of acetyl-CoA and NADH/FADH2, which respectively feed the citric acid cycle and the electron transport chain for energy (ATP) production.

Oxidative phosphorylation

Mitochondrial metabolic pathway that oxidizes NADH and FADH2 for ATP production through coupling to the electron transport chain.

Reactive carbonyl species

Reactive, unsaturated aldehydes or ketones produced by lipid peroxidation.

Unfolded protein response

Adaptive cellular mechanism that modulates the protein folding capacity of the endoplasmic reticulum to reduce unfolded protein load.

Uraemic cardiomyopathy

Condition of pathophysiological cardiac alterations observed in CKD patients, characterized by left ventricular hypertrophy, cardiac fibrosis, capillary rarefaction and cardiac dysfunction.

Uraemic retention solutes

Substances that accumulate in the body of patients with CKD owing to increased production and/or reduced kidney clearance.

Uraemic toxin

Uraemic retention solute with detrimental effects on organ and cell functions at CKD-relevant concentrations.

Vascular stiffness

Reduced vascular reactivity that contributes to cardiovascular risk.

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Noels, H., Jankowski, V., Schunk, S.J. et al. Post-translational modifications in kidney diseases and associated cardiovascular risk. Nat Rev Nephrol (2024). https://doi.org/10.1038/s41581-024-00837-x

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