PRESENTED BY
SYDNEY TANG

Presentation Summary

Writen by Jasna Trbojevic-Stankovic
Reviewed by Sydney Tang

Already approximately 25 centuries BC Shennong defined discoordination between the kidney and the heart as an ailment. Nowadays, we know that as high as 54% of all deaths among dialysis and transplant recipients are due to cardiovascular (CV) causes [1]. Population studies showed that albuminuria and estimated glomerular filtration (eGFR) rate are closely associated with all-cause as well as CV mortality [2]. In addition, sleep apnea strongly correlates with proteinuria in chronic kidney disease (CKD) patients [3]. In hemodialysis (HD) patients, for instance, there is a four-fold higher likelihood of sleep apnea and severe nocturnal hypoxemia as compared to matched controls [4]. Moreover, in peritoneal dialysis (PD) patients, sleep apnea is a risk predictor of CV morbidity and mortality [5].
Stroke risk in dialysis patients
The risk of developing a stroke dramatically increases from about two months before and stabilises only approximately six months after the commencement of incident dialysis [6]. One of the plausible mechanisms for this observation is a significant reduction in global and regional cerebral blood flow (CBF) induced by HD [7]. Furthermore, the CBF decline correlates with the intradialytic cognitive dysfunction [8].
Compared to HD, PD carries a 16% lower risk of hemorrhagic stroke, although the overall risks of all types of stroke including ischemic stroke is not different [9]. In addition, PD is associated with better cognitive functions and a lower incidence of dementia than HD [10, 11].

Figure 1: Overview of risk factors for stroke in patients with CKD [12, 13, 15]

Stroke risk in CKD patients
In CKD patients, the presence of anemia, hypoalbuminemia, malnutrition, uremia, and hyperhomocysteinemia all contribute to a higher incidence of stroke (Figure 1, [12]). It is known that high blood pressure (BP) is associated with a more rapid decline in eGFR [14]. However, both CKD and elevated BP are independent risk factors for incident stroke [15]. Interestingly, individuals with CKD with the lowest BP (<120 mmHg) are also at increased risk for stroke as compared to general population. CKD disrupts the blood-brain barrier and causes a 2-2.5-fold and a 5-fold increase in intracerebral microbleeds in mice and humans, respectively compared to controls (Figure 2). More patients in the dialysis cohort had increased microbleeds on follow-up magnetic resonance imaging after 1.5 years. These mechanisms might, at least in part, be explained by elevated urea-induced alterations in actin cytoskeleton and tight junction proteins in cultured endothelial cells [16].

Figure 2. CKD increases cerebral intracerebral microbleeds in mice and man [13, 15, 16]

Moreover, vascular age is another important risk factor for dialysis initiation or death in CKD. The gap between vascular age and chronological age may provide an alternative method to identify CKD patients at a high risk of progression to dialysis or death, as this gap is positively correlated with proteinuria and decreased baseline eGFR [17].

References

1. United States Renal Data System. 2018 USRDS annual data report: Epidemiology of kidney disease in the United States. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2018. https://www.usrds.org/2018/view/Default.aspx

2. Matsushita K, van der Velde M, Astor BC, 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. 2010;375(9731):2073-2081. DOI: 10.1016/S0140-6736(10)60674-5

3. Chan GC, Lam B, Yap DY, Ip MS, Lai KN, Tang SC. Proteinuria is associated with sleep apnea in chronic kidney disease. Nephrol Dial Transplant. 2016;31(5):772-779.DOI: 10.1093/ndt/gfv306

4. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034-2041. DOI: 10.1056/NEJMoa043104

5. Tang SC, Lam B, Yao TJ, et al. Sleep apnea is a novel risk predictor of cardiovascular morbidity and death in patients receiving peritoneal dialysis. Kidney Int. 2010;77(11):1031-1038. DOI: 10.1038/ki.2010.76

6. Murray AM, Seliger S, Lakshminarayan K, Herzog CA, Solid CA. Incidence of stroke before and after dialysis initiation in older patients. J Am Soc Nephrol. 2013;24(7):1166-1173. DOI: 10.1681/ASN.2012080841

7. Polinder-Bos HA, Garcia DV, Kuipers J, et al. Hemodialysis Induces an Acute Decline in Cerebral Blood Flow in Elderly Patients. J Am Soc Nephrol. 2018;29(4):1317-1325. DOI: 10.1681/ASN.2017101088.

8. Findlay MD, Dawson J, Dickie DA, et al. Investigating the Relationship between Cerebral Blood Flow and Cognitive Function in Hemodialysis Patients. J Am Soc Nephrol. 2019;30(1):147-158. DOI: 10.1681/ASN.2018050462

9. Boonpheng B, Thongprayoon C, Cheungpasitporn W. The comparison of risk of stroke in patients with peritoneal dialysis and hemodialysis: A systematic review and meta-analysis. J Evid Based Med. 2018;11(3):158-168. DOI: 10.1111/jebm.12315

10. Wolfgram DF, Szabo A, Murray AM, Whittle J. Risk of dementia in peritoneal dialysis patients compared with hemodialysis patients. Perit Dial Int. 2015;35(2):189-198. DOI: 10.3747/pdi.2014.00213

11. Neumann D, Mau W, Wienke A, Girndt M. Peritoneal dialysis is associated with better cognitive function than hemodialysis over a one-year course. Kidney Int. 2018;93(2):430-438. DOI: 10.1016/j.kint.2017.07.022

12. Saeed F, Kousar N, Qureshi K, Laurence TN. A review of risk factors for stroke in patients with chronic kidney disease. J Vasc Interv Neurol. 2009;2(1):126-131. PMID: 22518239

13. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 2000;36(3):646-661. DOI: 10.1053/ajkd.2000.16225

14. Weiner DE, Tighiouart H, Levey AS, et al. Lowest systolic blood pressure is associated with stroke in stages 3 to 4 chronic kidney disease. J Am Soc Nephrol. 2007;18(3):960-966. DOI: 10.1681/ASN.2006080858.

15. Tang S. Why is the risk of stroke so high in CKD and in dialysis patients? Oral presentation at 56th ERA-EDTA Congress; June 15, 2019. 

16. Lau WL, Nunes ACF, Vasilevko V, et al. Chronic Kidney Disease Increases Cerebral Microbleeds in Mouse and Man. Transl Stroke Res. 2019. DOI: 10.1007/s12975-019-00698-8.

17. Lin M, Chan GC, Chan KW, Lai KN, Tang SC. Vascular age is associated with the risk of dialysis or death in chronic kidney disease. Nephrology (Carlton). 2019. DOI: 10.1111/nep.13624.

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