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Noncardiovascular mortality in CKD: an epidemiological perspective

Key Points

  • Patients with chronic kidney disease (CKD) have increased risk of cardiovascular mortality

  • The increased noncardiovascular mortality in patients with CKD is also gaining increasing attention

  • The principal risk factors for noncardiovascular mortality in CKD are infection and malignancy

  • Various cardiovascular risk factors seem to be related to both cardiovascular and noncardiovascular mortality, including levels of fetuin-A, troponin T, and C-reactive protein as well as vitamin D deficiency and proteinuria

  • Inflammatory reactions and the uraemic milieu might explain the increased cardiovascular and noncardiovascular mortality in patients with CKD

Abstract

Patients with chronic kidney disease (CKD) have increased risk of all-cause mortality; the elevated cardiovascular mortality in patients with end-stage renal disease is particularly well documented. Lately, the increased noncardiovascular mortality in these patients has gained particular attention. In this article, both cardiovascular and noncardiovascular mortality in CKD are discussed, with specific attention paid to studies that provide details of noncardiovascular causes of death. Examples are provided of several cardiovascular risk factors that also seem to be associated with noncardiovascular mortality, including levels of fetuin-A, troponin T, and C-reactive protein, as well as vitamin D deficiency and proteinuria. Potential pathophysiological mechanisms (such as inflammatory reactions and the uraemic milieu) that might explain the increased cardiovascular and noncardiovascular mortality in CKD are also discussed. Future research should not only focus on preventing cardiovascular mortality, but also on studying noncardiovascular mortality and the potential link between causal pathways of cardiovascular mortality and noncardiovascular mortality in CKD.

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Figure 1: Distribution of causes of death in patients on dialysis according to renal registries in Asia,10 Europe,6 and the USA.5

References

  1. Wen, C. P. et al. All-cause mortality attributable to chronic kidney disease: a prospective cohort study based on 462,293 adults in Taiwan. Lancet 371, 2173–2182 (2008).

    PubMed  Google Scholar 

  2. Chadban, S. J. et al. Prevalence of kidney damage in Australian adults: the AusDiab kidney study. J. Am. Soc. Nephrol. 14 (Suppl. 2), S131–S138 (2003).

    PubMed  Google Scholar 

  3. Hallan, S. I. et al. International comparison of the relationship of chronic kidney disease prevalence and ESRD risk. J. Am. Soc. Nephrol. 17, 2275–2284 (2006).

    PubMed  Google Scholar 

  4. Coresh, J. et al. Prevalence of chronic kidney disease in the United States. JAMA 298, 2038–2047 (2007).

    CAS  PubMed  Google Scholar 

  5. United States Renal Data System (National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases). USRDS 2012 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States [online], (2013).

  6. ERA-EDTA Registry. ERA-EDTA Registry Annual Report 2011 [online], (2013).

  7. Steenkamp, R., Shaw, C. & Feest, T. UK Renal Registry 15th annual report: Chapter 5 survival and causes of death of UK adult patients on renal replacement therapy in 2011: national and centre-specific analyses. Nephron Clin. Pract. 123 (Suppl. 1), 93–123 (2013).

    PubMed  Google Scholar 

  8. Australia and New Zealand Dialysis and Transplant Registry. ANZDATA 2012 Annual Report [online], (2013).

  9. de Jager, D. J. et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 302, 1782–1789 (2009).

    CAS  PubMed  Google Scholar 

  10. Wakasugi, M., Kazama, J. J., Yamamoto, S., Kawamura, K. & Narita, I. Cause-specific excess mortality among dialysis patients: comparison with the general population in Japan. Ther. Apher. Dial. 17, 298–304 (2013).

    PubMed  Google Scholar 

  11. Raymond, N. T. et al. Elevated relative mortality risk with mild-to-moderate chronic kidney disease decreases with age. Nephrol. Dial. Transplant. 22, 3214–3220 (2007).

    PubMed  Google Scholar 

  12. Marks, A. et al. Chronic kidney disease, a useful trigger for proactive primary care? Mortality results from a large UK cohort. Fam. Pract. 30, 282–289 (2013).

    PubMed  Google Scholar 

  13. Matsushita, K. et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 375, 2073–2081 (2010).

    PubMed  PubMed Central  Google Scholar 

  14. Foley, R. N., Parfrey, P. S. & Sarnak, M. J. Clinical epidemiology of cardiovascular disease in chronic renal disease. Am. J. Kidney Dis. 32 (Suppl. 3), S112–S119 (1998).

    CAS  PubMed  Google Scholar 

  15. Genovesi, S. et al. Sudden death and associated factors in a historical cohort of chronic haemodialysis patients. Nephrol. Dial. Transplant. 24, 2529–2536 (2009).

    PubMed  Google Scholar 

  16. Foley, R. N., Parfrey, P. S. & Sarnak, M. J. Epidemiology of cardiovascular disease in chronic renal disease. J. Am. Soc. Nephrol. 9 (Suppl.), S16–S23 (1998).

    CAS  PubMed  Google Scholar 

  17. Levin, A. Clinical epidemiology of cardiovascular disease in chronic kidney disease prior to dialysis. Semin. Dial. 16, 101–105 (2003).

    PubMed  Google Scholar 

  18. Go, A. S., Chertow, G. M., Fan, D., McCulloch, C. E. & Hsu, C. Y. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med. 351, 1296–1305 (2004).

    CAS  PubMed  Google Scholar 

  19. Weiner, D. E. et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J. Am. Soc. Nephrol. 15, 1307–1315 (2004).

    PubMed  Google Scholar 

  20. Jager, K. J. et al. Cardiovascular and non-cardiovascular mortality in dialysis patients: where is the link? Kidney Int. Suppl. 1, 21–23 (2011).

    Google Scholar 

  21. Blacher, J. et al. Carotid arterial stiffness as a predictor of cardiovascular and all-cause mortality in end-stage renal disease. Hypertension 32, 570–574 (1998).

    CAS  PubMed  Google Scholar 

  22. Collins, A. J. Cardiovascular mortality in end-stage renal disease. Am. J. Med. Sci. 325, 163–167 (2003).

    PubMed  Google Scholar 

  23. Gansevoort, R. T. et al. Chronic kidney disease and cardiovascular risk: epidemiology, mechanisms, and prevention. Lancet 382, 339–352 (2013).

    PubMed  Google Scholar 

  24. Hackett, A. S. & Watnick, S. G. Withdrawal from dialysis in end-stage renal disease: medical, social, and psychological issues. Semin. Dial. 20, 86–90 (2007).

    PubMed  Google Scholar 

  25. Chan, H. W., Clayton, P. A., McDonald, S. P., Agar, J. W. M. & Jose, M. D. Risk factors for dialysis withdrawal: an analysis of the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry, 1999–2008 Clin. J. Am. Soc. Nephrol. 7, 775–781 (2012).

    PubMed  Google Scholar 

  26. Fried, L. F. et al. Kidney function as a predictor of noncardiovascular mortality. J. Am. Soc. Nephrol. 16, 3728–3735 (2005).

    CAS  PubMed  Google Scholar 

  27. Yeun, J. Y., Levine, R. A., Mantadilok, V. & Kaysen, G. A. C-reactive protein predicts all-cause and cardiovascular mortality in hemodialysis patients. Am. J. Kidney Dis. 35, 469–476 (2000).

    CAS  PubMed  Google Scholar 

  28. Owen, W. F. & Lowrie, E. G. C-reactive protein as an outcome predictor for maintenance hemodialysis patients. Kidney Int. 54, 627–636 (1998).

    CAS  PubMed  Google Scholar 

  29. Zimmermann, J., Herrlinger, S., Pruy, A., Metzger, T. & Wanner, C. Inflammation enhances cardiovascular risk and mortality in hemodialysis patients. Kidney Int. 55, 648–658 (1999).

    CAS  PubMed  Google Scholar 

  30. Zoccali, C. et al. Inflammation is associated with carotid atherosclerosis in dialysis patients. Creed Investigators. Cardiovascular Risk Extended Evaluation in Dialysis Patients. J. Hypertens. 18, 1207–1213 (2000).

    CAS  PubMed  Google Scholar 

  31. Iseki, K., Tozawa, M., Yoshi, S. & Fukiyama, K. Serum C-reactive protein (CRP) and risk of death in chronic dialysis patients. Nephrol. Dial. Transplant. 14, 1956–1960 (1999).

    CAS  PubMed  Google Scholar 

  32. Noh, H. et al. Serum C-reactive protein: a predictor of mortality in continuous ambulatory peritoneal dialysis patients. Perit. Dial. Int. 18, 387–394 (1998).

    CAS  PubMed  Google Scholar 

  33. Wanner, C., Drechsler, C. & Krane, V. C-reactive protein and uremia. Semin. Dial. 22, 438–441 (2009).

    PubMed  Google Scholar 

  34. Dellinger, R. P. et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock, 2012. Intensive Care Med. 39, 165–228 (2013).

    CAS  PubMed  Google Scholar 

  35. Wakasugi, M., Kawamura, K., Yamamoto, S., Kazama, J. J. & Narita, I. High mortality rate of infectious diseases in dialysis patients: a comparison with the general population in Japan. Ther. Apher. Dial. 16, 226–231 (2012).

    PubMed  Google Scholar 

  36. Sarnak, M. J. & Jaber, B. L. Mortality caused by sepsis in patients with end-stage renal disease compared with the general population. Kidney Int. 58, 1758–1764 (2000).

    CAS  PubMed  Google Scholar 

  37. Powe, N. R., Jaar, B., Furth, S. L., Hermann, J. & Briggs, W. Septicemia in dialysis patients: incidence, risk factors, and prognosis. Kidney Int. 55, 1081–1090 (1999).

    CAS  PubMed  Google Scholar 

  38. Wang, H. E., Gamboa, C., Warnock, D. G. & Muntner, P. Chronic kidney disease and risk of death from infection. Am. J. Nephrol. 34, 330–336 (2011).

    PubMed  PubMed Central  Google Scholar 

  39. Sarnak, M. J. & Jaber, B. L. Pulmonary infectious mortality among patients with end-stage renal disease. Chest 120, 1883–1887 (2001).

    CAS  PubMed  Google Scholar 

  40. Inamoto, H. et al. Incidence and mortality patterns of malignancy and factors affecting the risk of malignancy in dialysis patients. Nephron 59, 611–617 (1991).

    CAS  PubMed  Google Scholar 

  41. Birkeland, S. A., Lokkegaard, H. & Storm, H. H. Cancer risk in patients on dialysis and after renal transplantation. Lancet 355, 1886–1887 (2000).

    CAS  PubMed  Google Scholar 

  42. Iseki, K., Osawa, A. & Fukiyama, K. Evidence for increased cancer deaths in chronic dialysis patients. Am. J. Kidney Dis. 22, 308–313 (1993).

    CAS  PubMed  Google Scholar 

  43. Maisonneuve, P. et al. Cancer in patients on dialysis for end-stage renal disease: an international collaborative study. Lancet 354, 93–99 (1999).

    CAS  PubMed  Google Scholar 

  44. Weng, P. H. et al. Cancer-specific mortality in chronic kidney disease: longitudinal follow-up of a large cohort. Clin. J. Am. Soc. Nephrol. 6, 1121–1128 (2011).

    PubMed  PubMed Central  Google Scholar 

  45. Stewart, J. H. et al. Cancers of the kidney and urinary tract in patients on dialysis for end-stage renal disease: analysis of data from the United States, Europe, and Australia and New Zealand. J. Am. Soc. Nephrol. 14, 197–207 (2003).

    PubMed  Google Scholar 

  46. Buccianti, G. et al. Cancer among patients on renal replacement therapy: a population-based survey in Lombardy, Italy. Int. J. Cancer 66, 591–593 (1996).

    CAS  PubMed  Google Scholar 

  47. Wong, G. et al. Association of CKD and cancer risk in older people. J. Am. Soc. Nephrol. 20, 1341–1350 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Wong, G. et al. The risk of cancer in people with diabetes and chronic kidney disease. Nephrol. Dial. Transplant. 27, 3337–3344 (2012).

    CAS  PubMed  Google Scholar 

  49. Christensson, A. et al. Association of cancer with moderately impaired renal function at baseline in a large, representative, population-based cohort followed for up to 30 years. Int. J. Cancer 133, 1452–1458 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kantor, A. F., Hoover, R. N., Kinlen, L. J., McMullan, M. R. & Fraumenti, J. F. Jr. Cancer in patients receiving long-term dialysis treatment. Am. J. Epidemiol. 126, 370–376 (1987).

    CAS  PubMed  Google Scholar 

  51. Vajdic, C. M. et al. Cancer incidence before and after kidney transplantation. JAMA 296, 2823–2831 (2006).

    CAS  PubMed  Google Scholar 

  52. Newstead, C. G. Cancer risk in patients on dialysis. Lancet 354, 90–91 (1999).

    CAS  PubMed  Google Scholar 

  53. Iff, S. et al. Reduced Estimated GFR and Cancer Mortality. Am. J. Kidney Dis. 63, 23–30 (2014).

    PubMed  Google Scholar 

  54. Vamvakas, S., Bahner, U. & Heidland, A. Increased cancer incidence in terminal kidney failure: potential pathogenetic mechanisms [German]. Schweiz. Med. Wochenschr. 127, 597–604 (1997).

    CAS  PubMed  Google Scholar 

  55. Larsson, T. E. et al. Conjoint effects of serum calcium and phosphate on risk of total, cardiovascular, and noncardiovascular mortality in the community. Arterioscler. Thromb. Vasc. Biol. 30, 333–339 (2010).

    CAS  PubMed  Google Scholar 

  56. Di Iorio, B. et al. Sevelamer versus calcium carbonate in incident hemodialysis patients: results of an open-label 24-month randomized clinical trial. Am. J. Kidney Dis. 62, 771–778 (2013).

    CAS  PubMed  Google Scholar 

  57. Wang, A. Y. et al. Associations of serum fetuin-A with malnutrition, inflammation, atherosclerosis and valvular calcification syndrome and outcome in peritoneal dialysis patients. Nephrol. Dial. Transplant. 20, 1676–1685 (2005).

    CAS  PubMed  Google Scholar 

  58. Ooi, D. S., Veinot, J. P., Wells, G. A. & House, A. A. Increased mortality in hemodialyzed patients with elevated serum troponin T: a one-year outcome study. Clin. Biochem. 32, 647–652 (1999).

    CAS  PubMed  Google Scholar 

  59. Mehrotra, R. et al. Chronic kidney disease, hypovitaminosis D, and mortality in the United States. Kidney Int. 76, 977–983 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. den Elzen, W. P., van Manen, J. G., Boeschoten, E. W., Krediet, R. T. & Dekker, F. W. The effect of single and repeatedly high concentrations of C-reactive protein on cardiovascular and non-cardiovascular mortality in patients starting with dialysis. Nephrol. Dial. Transplant. 21, 1588–1595 (2006).

    CAS  PubMed  Google Scholar 

  61. Westenfeld, R. et al. Fetuin-A protects against atherosclerotic calcification in CKD. J. Am. Soc. Nephrol. 20, 1264–1274 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Moe, S. M. et al. Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD). Kidney Int. 67, 2295–2304 (2005).

    CAS  PubMed  Google Scholar 

  63. Ketteler, M. et al. Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361, 827–833 (2003).

    CAS  PubMed  Google Scholar 

  64. Hermans, M. M. et al. Association of serum fetuin-A levels with mortality in dialysis patients. Kidney Int. 72, 202–207 (2007).

    CAS  PubMed  Google Scholar 

  65. Johnson, P. A. et al. Cardiac troponin T as a marker for myocardial ischemia in patients seen at the emergency department for acute chest pain. Am. Heart J. 137, 1137–1144 (1999).

    CAS  PubMed  Google Scholar 

  66. Havekes, B. et al. Serum troponin T concentration as a predictor of mortality in hemodialysis and peritoneal dialysis patients. Am. J. Kidney Dis. 47, 823–829 (2006).

    CAS  PubMed  Google Scholar 

  67. Wang, A. Y. et al. Prognostic value of cardiac troponin T is independent of inflammation, residual renal function, and cardiac hypertrophy and dysfunction in peritoneal dialysis patients. Clin. Chem. 53, 882–889 (2007).

    PubMed  Google Scholar 

  68. Brandenburg, V. M., Vervloet, M. G. & Marx, N. The role of vitamin D in cardiovascular disease: from present evidence to future perspectives. Atherosclerosis 225, 253–263 (2012).

    CAS  PubMed  Google Scholar 

  69. Drechsler, C. et al. Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur. Heart J. 31, 2253–2261 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Dusso, A. S. Kidney disease and vitamin D levels: 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and VDR activation. Kidney Int. Suppl. 1, 136–141 (2011).

    CAS  Google Scholar 

  71. Murr, C. et al. Vitamin D deficiency parallels inflammation and immune activation, the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Clin. Chem. Lab. Med. 50, 2205–2212 (2012).

    CAS  PubMed  Google Scholar 

  72. Lange, N., Litonjua, A. A., Gibbons, F. K., Giovannucci, E. & Christopher, K. B. Pre-hospital vitamin D concentration, mortality, and bloodstream infection in a hospitalized patient population. Am. J. Med. 126, 640.e19–640.e27 (2013).

    CAS  Google Scholar 

  73. Ginde, A. A., Camargo, C. A. Jr & Shapiro, N. I. Vitamin D insufficiency and sepsis severity in emergency department patients with suspected infection. Acad. Emerg. Med. 18, 551–554 (2011).

    PubMed  Google Scholar 

  74. Venkatram, S. et al. Vitamin D deficiency is associated with mortality in the medical intensive care unit. Crit. Care 15, R292 (2011).

    PubMed  PubMed Central  Google Scholar 

  75. Bell, D. S. Protean manifestations of vitamin D deficiency, part 2: deficiency and its association with autoimmune disease, cancer, infection, asthma, dermopathies, insulin resistance, and type 2 diabetes. South. Med. J. 104, 335–339 (2011).

    PubMed  Google Scholar 

  76. Fiscella, K., Winters, P., Tancredi, D., Hendren, S. & Franks, P. Racial disparity in death from colorectal cancer: does vitamin D deficiency contribute? Cancer 117, 1061–1069 (2011).

    PubMed  Google Scholar 

  77. Yao, S. & Ambrosone, C. B. Associations between vitamin D deficiency and risk of aggressive breast cancer in African-American women. J. Steroid Biochem. Mol. Biol. 136, 337–341 (2013).

    CAS  PubMed  Google Scholar 

  78. Kim, H. J. et al. Vitamin D deficiency is correlated with poor outcomes in patients with luminal-type breast cancer. Ann. Surg. Oncol. 18, 1830–1836 (2011).

    PubMed  Google Scholar 

  79. Churilla, T. M., Brereton, H. D., Klem, M. & Peters, C. A. Vitamin D deficiency is widespread in cancer patients and correlates with advanced stage disease: a community oncology experience. Nutr. Cancer 64, 521–525 (2012).

    CAS  PubMed  Google Scholar 

  80. Drechsler, C. et al. Vitamin D status and clinical outcomes in incident dialysis patients: results from the NECOSAD study. Nephrol. Dial. Transplant. 26, 1024–1032 (2011).

    CAS  PubMed  Google Scholar 

  81. Nagata, M. et al. Prediction of cardiovascular disease mortality by proteinuria and reduced kidney function: pooled analysis of 39,000 individuals from 7 cohort studies in Japan. Am. J. Epidemiol. 178, 1–11 (2013).

    PubMed  Google Scholar 

  82. Bello, A. K. et al. Associations among estimated glomerular filtration rate, proteinuria, and adverse cardiovascular outcomes. Clin. J. Am. Soc. Nephrol. 6, 1418–1426 (2011).

    PubMed  PubMed Central  Google Scholar 

  83. Kidney Diseases: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int. Suppl. 3, 1–150 (2013).

  84. Wu, H. M., Tang, J. L., Cao, L., Sha, Z. H. & Li, Y. Interventions for preventing infection in nephrotic syndrome. Cochrane Database of Systematic Reviews, Issue 4, Art. No.: CD003964 http://dx.doi.org/10.1002/14651858CD003964.pub2.

  85. Cambier, J. F. & Ronco, P. Onco-nephrology: glomerular diseases with cancer. Clin. J. Am. Soc. Nephrol. 7, 1701–1712 (2012).

    CAS  PubMed  Google Scholar 

  86. Lagrand, W. K. et al. C-reactive protein as a cardiovascular risk factor: more than an epiphenomenon? Circulation 100, 96–102 (1999).

    CAS  PubMed  Google Scholar 

  87. Stenvinkel, P. et al. Strong association between malnutrition, inflammation, and atherosclerosis in chronic renal failure. Kidney Int. 55, 1899–1911 (1999).

    CAS  PubMed  Google Scholar 

  88. Kaysen, G. A. The microinflammatory state in uremia: causes and potential consequences. J. Am. Soc. Nephrol. 12, 1549–1557 (2001).

    CAS  PubMed  Google Scholar 

  89. Pupim, L. B., Himmelfarb, J., McMonagle, E., Shyr, Y. & Ikizler, T. A. Influence of initiation of maintenance hemodialysis on biomarkers of inflammation and oxidative stress. Kidney Int. 65, 2371–2379 (2004).

    CAS  PubMed  Google Scholar 

  90. Wu, C. C., Sytwu, H. K. & Lin, Y. F. Cytokines in diabetic nephropathy. Adv. Clin. Chem. 56, 55–74 (2012).

    CAS  PubMed  Google Scholar 

  91. Bloembergen, W. E. & Port, F. K. Epidemiological perspective on infections in chronic dialysis patients. Adv. Ren. Replace. Ther. 3, 201–207 (1996).

    CAS  PubMed  Google Scholar 

  92. Tiwari, S. et al. Prevalence and severity of vitamin D deficiency in patients with diabetic foot infection. Br. J. Nutr. 109, 99–102 (2013).

    CAS  PubMed  Google Scholar 

  93. Mora, J. R., Iwata, M. & von Andrian, U. H. Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685–698 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Liu, P. T. et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311, 1770–1773 (2006).

    CAS  PubMed  Google Scholar 

  95. Smeeth, L. et al. Risk of myocardial infarction and stroke after acute infection or vaccination. N. Engl. J. Med. 351, 2611–2618 (2004).

    CAS  PubMed  Google Scholar 

  96. Badiou, S. et al. Fine-tuning of the prediction of mortality in hemodialysis patients by use of cytokine proteomic determination. Clin. J. Am. Soc. Nephrol. 3, 423–430 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Cohen, G. & Horl, W. H. Immune dysfunction in uremia—an update. Toxins (Basel) 4, 962–990 (2012).

    CAS  Google Scholar 

  98. Mansouri, L., Paulsson, J. M., Moshfegh, A., Jacobson, S. H. & Lundahl, J. Leukocyte proliferation and immune modulator production in patients with chronic kidney disease. PLoS ONE 8, e73141 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Adesso, S. et al. The uremic toxin indoxyl sulphate enhances macrophage response to LPS. PLoS ONE 8, e76778 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Soubrane, C. et al. Influence of the uremic state on the development of malignancy. An experimental study in the rat. Am. J. Nephrol. 6, 363–368 (1986).

    CAS  PubMed  Google Scholar 

  101. Zaoui, P. & Hakim, R. M. Natural killer-cell function in hemodialysis patients: effect of the dialysis membrane. Kidney Int. 43, 1298–1305 (1993).

    CAS  PubMed  Google Scholar 

  102. Sun, C. Y., Chang, S. C. & Wu, M. S. Suppression of Klotho expression by protein-bound uremic toxins is associated with increased DNA methyltransferase expression and DNA hypermethylation. Kidney Int. 81, 640–650 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Abramovitz, L. et al. KL1 internal repeat mediates klotho tumor suppressor activities and inhibits bFGF and IGF-I signaling in pancreatic cancer. Clin. Cancer Res. 17, 4254–4266 (2011).

    CAS  PubMed  Google Scholar 

  104. Wolf, I. et al. Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin. Oncogene 29, 26–33 (2010).

    CAS  PubMed  Google Scholar 

  105. Katneni, R. & Hedayati, S. S. Central venous catheter-related bacteremia in chronic hemodialysis patients: epidemiology and evidence-based management. Nat. Clin. Pract. Nephrol. 3, 256–266 (2007).

    PubMed  Google Scholar 

  106. Janus, N., Vacher, L. V., Karie, S., Ledneva, E. & Deray, G. Vaccination and chronic kidney disease. Nephrol. Dial. Transplant. 23, 800–807 (2008).

    PubMed  Google Scholar 

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de Jager, D., Vervloet, M. & Dekker, F. Noncardiovascular mortality in CKD: an epidemiological perspective. Nat Rev Nephrol 10, 208–214 (2014). https://doi.org/10.1038/nrneph.2014.8

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