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5/18/2020
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DEBATECKD is a stroke risk factor: the case for
Professor Angela CWebsterMBBS FRACP FRCP [email protected]
Professor of Clinical Epidemiology, University of Sydney Specialist in Transplant Nephrology, Westmead Hospital, Sydney, Australia
Disclosures
• No financial relationships or payments of any kind
• No off label drug use mentions
• No private practice
• Employed by University of Sydney and WesternSydney local health district (Westmead Hospital)
CKD is a stroke risk factorWebsterDO NOT
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5/18/2020
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Debunking the myth that CKD and stroke just share risk factors
• CKD is not a confounder of risk factors for stroke
• CKD is an independent predictor of stroke death
• There is a direct CKD/brain function relationship
• (There are questions yet to find answers)
Who do nephrologists see?
Nomenclature of CKD
The Lancet 389 (10075), 1238‐1252DO NOT
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Who nephrologists see
The Lancet 389 (10075), 1238‐1252
ESKD
Peritoneal dialysis Haemodialysis Transplantation Supportive care
Premature death x10 more likely than progressing to dialysis
Stroke incidence by GFR and proteinuriaSystematic review 83 studies
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Risk by GFR and proteinuria threshold
GFR (ml/min/1.73m2) ACR (mg/mmol)
Relative risk Stroke
10 year stroke risk
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So stroke just goes up with age and accumulated known risk factors right?
• Causes of CKD include hypertension, diabetes, vascular disease, so the longer people have these the more likely they are to stroke and CKD is incidental?
15
1020
5010
0
30 40 50 60 70 80 30 40 50 60 70 80 30 40 50 60 70 80
(Relative) risk of hospitalisation with stroke in ESKD
Ischemic stroke Intracerebral hemorrhage All-cause stroke
male
female
Inci
denc
eR
ate
Rat
io
Age (years)
No – greater excess risk at lower ages
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Mechanisms?
>130,000 patients with Atrial Fibrillation in Danish Registries
Prevalence
• 9.6% (Taiwan) (Shih Circulation 2016)
• 10% (Fresenius Europe) (Brancaccio Am J Neph 2016)
• 14.5% (Medicare 2000‐2005) (Wetmore JASN 2015)
• 21% (Glasgow, 2007‐2012) (Findlay Stroke 2015)
• 26.5% (Vienna) (Konigsbrugge PlosOne 2017)
• 12.4% of all ESKD including transplants (Scottish Renal Registry)
Is it all this just
confounding by AF?
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Is CKD a risk factor for all kinds of stroke?
• 50% CKD and dialysis patients had microbleeds compared to 10% age matched controls
• Progression (MRI) greatest in dialysis folk after1.5 years
• Actin cytoskeleton and tight junction alteration?
There are effects of dialysis itself
• N=12
• O15[H2O] PET‐CT
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Effect of primary and secondary prevention proven in the gen pop?
• Lipids
• Blood pressure
• Obesity management
• Smoking
Effect of primary and secondary prevention proven in the gen pop?
• Lipids
• Blood pressure
• Obesity management
• Smoking
Statins of limited or no value in dialysis, do help post transplant
ACE‐I and ARB advantages limited in non proteinuric CKD and in
proteinuric ESKD
J shaped survival curves, BMI 22 worse than 30
Data?
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Debunking the myth that CKD and stroke just share risk factors
• CKD is not a confounder of risk factors for stroke
– it is an effect modifier (interaction)
• CKD is an independent predictor of stroke death
• There is a direct CKD/brain function relationship
• (There are questions yet to find answers)
Debunking the myth that CKD and stroke just share risk factors
• CKD is not a confounder of risk factors for stroke
• CKD is an independent predictor of stroke death
• There is a direct CKD/brain function relationship
• (There are questions yet to find answers)DO NOT
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Relative mortality
Stroke. 2019;50(2):487‐490
Little to no improvement over era
Cumulative mortality since ESKDStroke death risk increased by
• Age• Female sex• Known prior vascular
disease• Dialysis vintage• Obesity• ESKD caused by
hypertension ordiabetes
Risk decreased by
• Polycystic kidney disease
• Prior cancer• Transplantation
de la Mata et al. BMJ Open 2019;9:e026263DO NOT
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• >113,000 ICH, >1400 US centres
• 1/3 had CKD (GFR <60ml/min/1.73m^2)
• Associated to poorer care (KPIs)
• Substantially higher mortality
– In hospital
– Hospice/care home discharge
Inequality in Care and Differencesin Outcome Following Stroke in People Wi th End-Stage Renal Disease
M a r k D . Findlay1 • 2 , Jesse Daw so n1 • 2 , Rachael Mac l saac1, A la n G . Ja rd in e1 • 2 ,
M a r y J o a n Ma c l eod3• 5 , W e n d y Metca l f e4• 6 , J a m i e P. Tray nor2 • 6 , and Pat ric k B. M ark1 • 2
Management, n [o/o] Non ESRDStroke
ESRD stroke
Admitted to Stroke unit 47619 [78.0] 189 [67.5] 0.002
Thrombolysis - IS only 2487 [4.8] 10 [3.9] 0.649
Aspirin - IS only 43194 [83.7] 190 [74.5] <0.001
Swallow screen 48692 [79.7] 214 [76.4] 0.191
Brain Imaging 59680 [97.7] 278 [99.3] 0.257
REPORTSKIReports.orgDO N
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Gen Pop‐ ASU
ESRD‐ no ASU
Gen Pop‐ no ASU
ESRD‐ASU
Specialised stroke services work‐ Even for people with ESKD
For ESKD patients, risk of death was lower if managed in stroke unit HR 0.68, (CI 0.55‐0.84) independent of other risk factors
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Debunking the myth that CKD and stroke just share risk factors
• CKD is not a confounder of risk factors for stroke
• CKD is an independent predictor of stroke death
– Poorer care, poorer outcomes
• There is a direct CKD/brain function relationship
• (There are questions yet to find answers)
Debunking the myth that CKD and stroke just share risk factors
• CKD is not a confounder of risk factors for stroke
• CKD is an independent predictor of stroke death
• There is a direct CKD/brain function relationship
• (There are questions yet to find answers)DO NOT
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Cognition and CKD
HAEMODIALYSIS
42 studies (3,522 participants)
Comparison population Studies Participants
People on peritoneal dialysis 13 1144
People with chronic kidney disease 8 629
People with non dialysed end stage kidney disease 7 248
Generalpopulation 32 2231
CKD
TRANSPLANT 11 studies (998 participants) included in datasynthesis
Comparisonpopulation Studies Participants
People without CKD or ESKD 6 320
People withCKD 2 129
People withESKD 3 337
Before and after transplant 7 149
Comparisonpopulation Studies NPeople on peritoneal dialysis 13 1144People with chronic kidneydisease
8 629
People with nondialyzed chronickidney disease General population
7
32
248
2231
Peritoneal dialysis, 42 studies, in 3522
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For CKD
Some domains impacted early
Power an issue
What does this mean in context?language – Boston Naming Test (BNT)
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Dialysis patients
Clinical Applicability
24‐34s =“Average >48s = “Extremely low performance”
performance”
Gen pop HD Nd ESKD
0 32.1 50.1 62.4
Time to completion in seconds(longer time to completion = poorer orientation and attention)
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Transplantation ‐ Cognitive effects of CKD are reversible?
Masso et al, unpub
Evidence of improvement within individuals from pre to post transplant
Debunking the myth that CKD and stroke just share risk factors
• CKD is not a confounder of risk factors for stroke
• CKD is an independent predictor of stroke death
• There is a direct CKD/brain function relationship
• (There are questions yet to find answers)DO NOT
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5/18/2020
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Bringing this all together:
• Proteinuria not just GFR
• Increased incidence which increases as GFR falls and as proteinuria increases
• Excess burden greatest for women, and younger people
• Disproportionate contribution of haemorrhagic stroke
• Health services factors contribute– issues of equity and access
• Shared risk factors but not shared response to interventions
• Elements of reversibility
Debunking the myth: Evidence that:
• CKD is not a confounder of risk
factors for stroke
• CKD is an independent predictor
of stroke death
• There is a direct CKD/brain
function relationship
• (There are questions yet to find
answers)
Thank you. Everything is connected.
Acknowledgements
Phil Masson, Royal Free
Paddy Marks, Glasgow
Patrick Kelly and Nicole de la Mata, Sydney
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