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Association of advanced age with concentrations of uraemic toxins in CKD

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Abstract

To our knowledge, there are no studies on advanced chronic kidney disease (CKD) analysing the impact of ageing on serum concentrations of uraemic toxins while adjusting for renal function. Knowledge of this feature, however, could influence prognostic assessment and therapeutic decision-making, e.g. about when to start dialysis or how intensive it should be. Indeed, the slowing down of metabolism with age may result in lower uraemic toxin concentrations, hence reducing their toxic effects. In this case, a later start of dialysis or less intensive dialysis may become justified in an already fragile population that might enjoy a better quality of life without a survival disadvantage with conservative treatment. We assessed the impact of advancing age on uraemic solute concentrations [blood, urea, nitrogen (BUN), uric acid, creatinine, asymmetric and symmetric dimethylarginine (ADMA and SDMA), β2-microglobulin and a large array of protein-bound solutes] by matching 126 maintenance haemodialysis patients subdivided into two age-groups, younger vs. older (using the median as cut-off: 72 years). Concentrations were compared after age stratification and were matched with patient and dialysis characteristics. In addition, 93 non-dialysed CKD patients (median as cut-off: 70 years), with a comparable average estimated glomerular filtration rate (eGFR) between younger and older age-groups, were analysed. In haemodialysis patients, carboxy-methyl-furanpropionic acid (CMPF) levels were markedly higher and BUN and uric acid borderline lower in the older age-group. All other solutes showed no difference. At multifactor analysis, the concentration of several uraemic toxins was associated with residual renal function and protein intake in the overall haemodialysis group and the younger group, but the association with most solutes, especially those protein-bound, was lost in the older age-group. No differences were found in non-dialysed CKD patients. It was concluded that in this CKD population concentrations of uraemic toxins did not change substantially with calendar age.

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References

  1. Boult C, Altmann M, Gilbertson D, Yu C, Kane RL (1996) Decreasing disability in the 21st century: the future effects of controlling six fatal and nonfatal conditions. Am J Public Health 86:1388–1393

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  2. van Oostrom SH, Picavet HS, de Bruin Sr et al (2014) Multimorbidity of chronic diseases and health care utilization in general practice. BMC Fam Pract 15:61

  3. Wetzels JF, Kiemeney LA, Swinkels DW, Willems HL, den Heijer M (2007) Age- and gender-specific reference values of estimated GFR in Caucasians: the Nijmegen Biomedical Study. Kidney Int 72:632–637

    Article  PubMed  CAS  Google Scholar 

  4. Hemmelgarn BR, Zhang J, Manns BJ et al (2006) Progression of kidney dysfunction in the community-dwelling elderly. Kidney Int 69:2155–2161

    Article  PubMed  CAS  Google Scholar 

  5. Glassock RJ, Winearls C (2008) Screening for CKD with eGFR: doubts and dangers. Clin J Am Soc Nephrol 3:1563–1568

    Article  PubMed  PubMed Central  Google Scholar 

  6. Anderson S, Halter JB, Hazzard WR et al (2009) Prediction, progression, and outcomes of chronic kidney disease in older adults. J Am Soc Nephrol 20:1199–1209

    Article  PubMed  CAS  Google Scholar 

  7. Canaud B, Tong L, Tentori F et al (2011) Clinical practices and outcomes in elderly hemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Clin J Am Soc Nephrol 6:1651–1662

    Article  PubMed  PubMed Central  Google Scholar 

  8. Vanholder R, Schepers E, Pletinck A, Nagler EV, Glorieux G (2014) The uremic toxicity of indoxyl sulfate and p-cresyl sulfate: a systematic review. J Am Soc Nephrol 25(9):1897–1907

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Meyer TW, Hostetter TH (2007) Uremia. N Engl J Med 357:1316–1325

    Article  PubMed  CAS  Google Scholar 

  10. Vanholder R, Massy Z, Argiles A, Spasovski G, Verbeke F, Lameire N (2005) Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transplant 20:1048–1056

    Article  PubMed  CAS  Google Scholar 

  11. Cheung AK, Rocco MV, Yan G et al (2006) Serum beta-2 microglobulin levels predict mortality in dialysis patients: results of the HEMO study. J Am Soc Nephrol 17:546–555

    Article  PubMed  CAS  Google Scholar 

  12. Liabeuf S, Lenglet A, Desjardins L et al (2012) Plasma beta-2 microglobulin is associated with cardiovascular disease in uremic patients. Kidney Int 82:1297–1303

    Article  PubMed  CAS  Google Scholar 

  13. Liabeuf S, Barreto DV, Barreto FC et al (2010) Free p-cresylsulphate is a predictor of mortality in patients at different stages of chronic kidney disease. Nephrol Dial Transplant 25:1183–1191

    Article  PubMed  CAS  Google Scholar 

  14. Barreto FC, Barreto DV, Liabeuf S et al (2009) Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients. Clin J Am Soc Nephrol 4:1551–1558

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Meijers BK, Claes K, Bammens B et al (2010) p-Cresol and cardiovascular risk in mild-to-moderate kidney disease. Clin J Am Soc Nephrol 5:1182–1189

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  16. Kielstein JT, Zoccali C (2005) Asymmetric dimethylarginine: a cardiovascular risk factor and a uremic toxin coming of age? Am J Kidney Dis 46:186–202

    Article  PubMed  CAS  Google Scholar 

  17. Meijers BK, Evenepoel P (2011) The gut-kidney axis: indoxyl sulfate, p-cresyl sulfate and CKD progression. Nephrol Dial Transplant 26:759–761

    Article  PubMed  CAS  Google Scholar 

  18. Schepers E, Glorieux G, Vanholder R (2010) The gut: the forgotten organ in uremia? Blood Purif 29:130–136

    Article  PubMed  Google Scholar 

  19. Schmucker DL (1998) Aging and the liver: an update. J Gerontol A Biol Sci Med Sci 53:B315–B320

    Article  PubMed  CAS  Google Scholar 

  20. Kinirons MT, O’Mahony MS (2004) Drug metabolism and ageing. Br J Clin Pharmacol 57:540–544

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  21. Hopkins MJ, Sharp R, Macfarlane GT (2001) Age and disease related changes in intestinal bacterial populations assessed by cell culture, 16S rRNA abundance, and community cellular fatty acid profiles. Gut 48:198–205

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  22. Sydow K, Fortmann SP, Fair JM et al (2010) Distribution of asymmetric dimethylarginine among 980 healthy, older adults of different ethnicities. Clin Chem 56:111–120

    Article  PubMed  CAS  Google Scholar 

  23. Kielstein JT, Bode-Boger SM, Frolich JC, Ritz E, Haller H, Fliser D (2003) Asymmetric dimethylarginine, blood pressure, and renal perfusion in elderly subjects. Circulation 107:1891–1895

    Article  PubMed  Google Scholar 

  24. Schulze F, Maas R, Freese R, Schwedhelm E, Silberhorn E, Boger RH (2005) Determination of a reference value for N(G), N(G)-dimethyl-l-arginine in 500 subjects. Eur J Clin Invest 35:622–626

    Article  PubMed  CAS  Google Scholar 

  25. Matrai Z, Nemeth J, Miklos K, Szabo Z, Masszi T (2009) Serum beta2-microglobulin measured by immunonephelometry: expression patterns and reference intervals in healthy adults. Clin Chem Lab Med 47:585–589

    Article  PubMed  CAS  Google Scholar 

  26. Kuzuya M, Ando F, Iguchi A, Shimokata H (2002) Effect of aging on serum uric acid levels: longitudinal changes in a large Japanese population group. J Gerontol A Biol Sci Med Sci 57:M660–M664

    Article  PubMed  Google Scholar 

  27. Marquez IO, Tambra S, Luo FY et al (2011) Contribution of residual function to removal of protein-bound solutes in hemodialysis. Clin J Am Soc Nephrol 6:290–296

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Eloot S, Schepers E, Barreto DV et al (2011) Estimated glomerular filtration rate is a poor predictor of concentration for a broad range of uremic toxins. Clin J Am Soc Nephrol 6:1266–1273

    Article  PubMed  PubMed Central  Google Scholar 

  29. Neirynck N, Eloot S, Glorieux G et al (2012) Estimated glomerular filtration rate is a poor predictor of the concentration of middle molecular weight uremic solutes in chronic kidney disease. PLoS ONE 7:e44201

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  30. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41

    Article  PubMed  CAS  Google Scholar 

  31. Fagugli RM, De Smet R, Buoncristiani U, Lameire N, Vanholder R (2002) Behavior of non-protein-bound and protein-bound uremic solutes during daily hemodialysis. Am J Kidney Dis 40:339–347

    Article  PubMed  CAS  Google Scholar 

  32. Daugirdas JT (1993) Second generation logarithmic estimates of single-pool variable volume Kt/V: an analysis of error. J Am Soc Nephrol 4:1205–1213

    PubMed  CAS  Google Scholar 

  33. Jindal KK, Goldstein MB (1988) Urea kientic modeling in chronic hemodialysis: benefits, problems, and practical solutions. Semin Dial 1:82–85

    Article  Google Scholar 

  34. Eloot S, Van Biesen W, Glorieux G, Neirynck N, Dhondt A, Vanholder R (2013) Does the adequacy parameter Kt/V(urea) reflect uremic toxin concentrations in hemodialysis patients? PLoS One 8:e76838

    Article  PubMed  PubMed Central  Google Scholar 

  35. Stevens LA, Coresh J, Schmid CH et al (2008) Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD. Am J Kidney Dis 51:395–406

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Deneva-Koycheva TI, Vladimirova-Kitova LG, Angelova EA, Tsvetkova TZ (2011) Plasma asymmetric dimethylarginine levels in healthy people. Folia Med (Plovdiv) 53:28–33

    Google Scholar 

  37. Isobe C, Abe T, Terayama Y (2010) Decrease in asymmetrical dimethylarginine, an endogenous nitric oxide synthase inhibitor, in cerebrospinal fluid during elderly aging and in patients with sporadic form of amyotrophic lateral sclerosis. Neurosignals 18:43–48

    Article  PubMed  CAS  Google Scholar 

  38. Schnabel R, Blankenberg S, Lubos E et al (2005) Asymmetric dimethylarginine and the risk of cardiovascular events and death in patients with coronary artery disease: results from the AtheroGene Study. Circ Res 97:e53–e59

    Article  PubMed  CAS  Google Scholar 

  39. Stanga Z, Nock S, Medina-Escobar P, Nydegger UE, Risch M, Risch L (2013) Factors other than the glomerular filtration rate that determine the serum beta-2-microglobulin level. PLoS One 8:e72073

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  40. Viaene L, Thijs L, Jin Y et al (2014) Heritability and clinical determinants of serum indoxyl sulfate and p-cresyl sulfate, candidate biomarkers of the human microbiome enterotype. PLoS ONE 9:e79682

    Article  PubMed  PubMed Central  Google Scholar 

  41. Davies SJ, Davenport A (2014) The role of bioimpedance and biomarkers in helping to aid clinical decision-making of volume assessments in dialysis patients. Kidney Int 86:489–496

    Article  PubMed  Google Scholar 

  42. Kyle UG, Genton L, Hans D, Karsegard L, Slosman DO, Pichard C (2001) Age-related differences in fat-free mass, skeletal muscle, body cell mass and fat mass between 18 and 94 years. Eur J Clin Nutr 55:663–672

    Article  PubMed  CAS  Google Scholar 

  43. Dittmar M, Reber H, Hofmann G (2001) Age-related decline in body cell mass in elderly men and women, determined by a noninvasive nuclear technique: effects of physical activity and dietary potassium intake. Am J Hum Biol 13:204–211

    Article  PubMed  CAS  Google Scholar 

  44. Nicholls A, Scott JT (1972) Effect of weight-loss on plasma and urinary levels of uric acid. Lancet 2:1223–1224

    Article  PubMed  CAS  Google Scholar 

  45. Garg JP, Chasan-Taber S, Blair A et al (2005) Effects of sevelamer and calcium-based phosphate binders on uric acid concentrations in patients undergoing hemodialysis: a randomized clinical trial. Arthritis Rheum 52:290–295

    Article  PubMed  CAS  Google Scholar 

  46. Cupisti A, Saba A, D’Alessandro C et al (2009) Dimethylarginine levels and nutritional status in hemodialysis patients. J Nephrol 22:623–629

    PubMed  CAS  Google Scholar 

  47. Glass RL, Krick TP, Sand DM, Rahn CH, Schlenk H (1975) Furanoid fatty acids from fish lipids. Lipids 10:695–702

    Article  PubMed  CAS  Google Scholar 

  48. Hannemann K, Puchta V, Simon E, Ziegler H, Ziegler G, Spiteller G (1989) The common occurrence of furan fatty acids in plants. Lipids 24:296–298

    Article  PubMed  CAS  Google Scholar 

  49. Mabuchi H, Nakahashi H (1988) A major inhibitor of phenytoin binding to serum protein in uremia. Nephron 48:310–314

    Article  PubMed  CAS  Google Scholar 

  50. Mabuchi H, Nakahashi H (1988) Inhibition of hepatic glutathione S-transferases by a major endogenous ligand substance present in uremic serum. Nephron 49:281–283

    Article  PubMed  CAS  Google Scholar 

  51. Sun H, Frassetto L, Benet LZ (2006) Effects of renal failure on drug transport and metabolism. Pharmacol Ther 109:1–11

    Article  PubMed  CAS  Google Scholar 

  52. Sun H, Huang Y, Frassetto L, Benet LZ (2004) Effects of uremic toxins on hepatic uptake and metabolism of erythromycin. Drug Metab Dispos 32:1239–1246

    Article  PubMed  CAS  Google Scholar 

  53. Itoh Y, Ezawa A, Kikuchi K, Tsuruta Y, Niwa T (2012) Protein-bound uremic toxins in hemodialysis patients measured by liquid chromatography/tandem mass spectrometry and their effects on endothelial ROS production. Anal Bioanal Chem 403:1841–1850

    Article  PubMed  CAS  Google Scholar 

  54. Sassa T, Matsuno H, Niwa M et al (2000) Measurement of furancarboxylic acid, a candidate for uremic toxin, in human serum, hair, and sweat, and analysis of pharmacological actions in vitro. Arch Toxicol 73:649–654

    Article  PubMed  CAS  Google Scholar 

  55. Muller MJ, Geisler C, Pourhassan M, Gluer CC, Bosy-Westphal A. Assessment and definition of lean body mass deficiency in the elderly. Eur J Clin Nutr (in press)

  56. Garcia-Garcia FJ, Carcaillon L, Fernandez-Tresguerres J et al (2014) A new operational definition of frailty: the frailty trait scale. J Am Med Dir Assoc 15:371

    Article  PubMed  Google Scholar 

  57. Kelaiditi E, Cesari M, Canevelli M et al (2013) Cognitive frailty: rational and definition from an (I.A.N.A./I.A.G.G.) international consensus group. J Nutr Health Aging 17:726–734

    Article  PubMed  CAS  Google Scholar 

  58. Johansen KL, Dalrymple LS, Delgado C et al (2014) Association between body composition and frailty among prevalent hemodialysis patients: a US Renal Data System special study. J Am Soc Nephrol 25:381–389

    Article  PubMed  PubMed Central  Google Scholar 

  59. Hallan SI, Matsushita K, Sang Y et al (2012) Age and association of kidney measures with mortality and end-stage renal disease. JAMA 308:2349–2360

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

The authors are indebted to M. Van Landschoot and M.A. Waterloos for their technical assistance, and to C. Vinck for the language revision of the text.

Conflict of interest

None of the authors has a conflict of interest.

Ethical approval

All patients were Caucasian. Both studies were approved by the local ethical committees and performed in accordance with the ethical principles of the Declaration of Helsinki.

Informed consent

All included patients gave their written informed consent.

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Author notes

    Authors and Affiliations

    1. Service of Nephrology, University Hospital Centre “Mother Teresa”, Tirana, Albania

      Merita Rroji

    2. Nephrology Section, Department of Internal Medicine, Ghent University Hospital, 0K12, De Pintelaan, 185, B9000, Ghent, Belgium

      Sunny Eloot, Annemie Dhondt, Wim Van Biesen, Griet Glorieux, Nathalie Neirynck & Raymond Vanholder

    3. Department of Geriatric Medicine, Ghent University Hospital, Ghent, Belgium

      Nele Vandennoortgate

    4. INSERM Unit 1088, Jules Verne University of Picardie, Amiens, France

      Sophie Liabeuf & Ziad Massy

    5. Division of Ckinical Pharmacology, Clinical Research Center, Amiens University Hospital, 80054, Amiens, France

      Sophie Liabeuf

    6. Division of Nephrology, Ambroise Paré Hospital, AP-HP, Paris-Ile-de-France-Ouest University (UVSQ), Boulogne-Billancourt, Paris, France

      Ziad Massy

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    1. Merita Rroji
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    Correspondence to Sunny Eloot.

    Additional information

    M. Rroji and S. Eloot contributed equally to this study.

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    Rroji, M., Eloot, S., Dhondt, A. et al. Association of advanced age with concentrations of uraemic toxins in CKD. J Nephrol 29, 81–91 (2016). https://doi.org/10.1007/s40620-015-0195-z

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    • DOI: https://doi.org/10.1007/s40620-015-0195-z

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