Hemodialysis induces an

acute decline in cerebral

perfusion in elderly patients

Casper Franssen

Dept. of Nephrology

University Medical Center Groningen

Dutch Nephrology days 2019

Groningen

Kidney

Center

Disclosures/

Disclosure belangen spreker

(potentiële) belangenverstrengeling Zie hieronder

Voor bijeenkomst mogelijk relevante relaties met bedrijven

Bedrijfsnamen

• Sponsoring of onderzoeksgeld Amgen, Fresenius

• Honorarium of andere (financiële)

vergoeding

-

• Aandeelhouder -

• Andere relatie, namelijk … -

Groningen

Kidney

Center

Publication Groningen

Kidney

Center

J Am Soc Nephrol 2018;29:1317-1325

Major problems with conventional HD Groningen

Kidney

Center

Large fluctuations, e.g. in hydration

status: frequent hemodynamic

instability

High cardiovascular morbidity and

mortality, mainly cardiac &

cerebrovascular

Concept: HD as a risk factor Groningen

Kidney

Center

HD also a risk factor for cerebral damage? Groningen

Kidney

Center

Transition to HD is associated with

• decline in cognitive function1

• rise in stroke incidence2

1 Kurella Tamura, Kidney Int 2017; 2 Murray, JASN 2013; 3 Eldehni, JASN 2015;10:1408-17

Progression of white matter lesions

during 1st year of HD. This was

attenuated with cool dialysate3

Hypothesis Groningen

Kidney

Center

The repetitive circulatory stress of

HD induces induces (cumulative)

ischemic cerebral injury

But .. the mechanism by which HD could

contribute to brain injury is unknown

Study aims Groningen

Kidney

Center

1. To study the acute effect of hemodialysis on global

and regional cerebral blood flow

1MacEwen, JASN 2017; Yoon, Front Physiol 2012; Hata, Stroke 1994;

Stefanidis, Clin Nephrol 2005; Metry, Am J Kidney Dis 2002; Eldehni, JASN 2015

2. Explore associations between HD-related factors

and cerebral blood flow1: • MAP

• UF-volume & UF-rate

• pCO2 & pH

• Hematocrit

• Body temperature

Patients Groningen

Kidney

Center

Inclusion criteria:

• age ≥65 years

• arteriovenous fistula without

recirculation

0,000

10,000

20,000

30,000

0 100 200 300

Gray Matter (kBq/cc)

0

50000

100000

0 100 200 300

whole-blood (Bq/cc)

Exclusion criteria:

• history of dementia, CVA

• >70% internal carotid artery

stenosis

Methods - [15O] H2O PET-CT scans Groningen

Kidney

Center

T1: before HD

(mean -18 min)

T2: early during HD

(mean +21 min)

T3: at the end of HD

(mean +209 min)

Dialysis settings:

- Constant UF-rate

- Dialysate temp. 36.5°C

Results - Patients Groningen

Kidney

Center

Patient characteristics N=12

Age 75.4 ± 5.2

Male sex 7 (58%)

Dialysis vintage (months) 47 (range 11-319)

Diabetes 3 (25%)

Fazekas score of white matter lesions:

0 No WML 1 (8%)

1-2 Multiple punctate - confluent WML 9 (75%)

3 Large confluent WML 2 (17%)

Microbleeds 7 (58%)

Results - Global CBF change Groningen

Kidney

Center

Before (T1) versus at the end of HD (T3):

mL/100g/min %

Global CBF -4.1 (-7.3; -0.9) * -10.3

* p<0.05

Results - Regional CBF change Groningen

Kidney

Center

Before (T1) versus at the end of HD (T3):

mL/100g/min %

Frontal -5.1 (-9.5; -0.6) * -10.9

Parietal -4.7 (-8.7; -0.8) * -11.3

Temporal -4.0 (-7.4; -0.6) * -9.7

Occipital -4.4 (-8.4; -0.3) * -9.2

Cerebellum -5.0 (-9.2;-0.8) * -9.8

Thalamus -5.5 (-11.1; 0.2) -10.2

* p<0.05

HD-related factors Groningen

Kidney

Center

Factors associated with lower

cerebral perfusion:

• Higher UF volume

• Higher blood pH (only at T2)

• Higher tympanic temperature

Adverse event Groningen

Kidney

Center

A patient lost consciousness due to

dialysis hypotension shortly after

the 3rd scan

Full recovery without sequelae

CBF decreased 20% from T1 to T3

Conclusion Groningen

Kidney

Center

1. Conventional HD induces a decline in

global CBF of 10% in elderly patients

2. A higher pH, body temperature and

UF volume were associated with

lower CBF

Repetitive intradialytic decreases in CBF may be

one of the mechanisms by which HD induces

cerebral ischemic injury

I

How do our results fit in recent literature? Groningen

Kidney

Center

Transcranial

Doppler: velocity of

art cerebri media Mean flow velocity decreased 10% (n=82)

Fall in flow velocity correlated significantly with

UF-volume & intradialytic decline in cognition

At 12 months of follow-up, the decline in CBF correlated with:

• progression of white matter lesions

• Lower global and executive function

JASN 2019

Open questions Groningen

Kidney

Center

2. What exactly causes the decline in CBF?

On a background of

- macro- & microvascular lesions

- autonomic dysfunction

- endothelial dysfunction

Inflammation & endothelial dysfunction

- angiopoeitin-2

Hemodynamic changes/ hypovolemia:

- UF

- Temperature

Acid-base & electrolyte changes

- pH

1. Are repetitive HD-induced CBF declines causally

related to ischemic brain lesions & cognitive decline?

Polinder et al. J Cerebr blood flow Metabol 2018

Future research Groningen

Kidney

Center

• Study the effect of a lower UF rate & slower

correction of acidosis on CBF (nocturnal HD)

• Study link between HD-induced inflammation/

endothelial dysfunction & organ perfusion

Ultimate goal: to identify HD-related factors that are involved

in CBF decline ⇾ HD regimen that minimizes cerebrovascular

(and cardiac) stress

What can we do in the meantime? Groningen

Kidney

Center

1. Use cool dialysate 2. Renal transplantation

Warm

C

ool

Eldheni et al. CJASN 2015;10:1408-17

Transplantation 2015

3. Cognitive & exercise training

KI reports 2017

JASN 2019

Acknowledgements Groningen

Kidney

Center

Participating patients

Dept. Nephrology: Casper Franssen - study PI

Carlo Gaillard, Ron Gansevoort.

Dialysis Center Groningen Hannie Kuiper, Ralf Westerhuis

Students: Rozemarijn, Renske, Marleen, Thom, Brandt, Lara

Dept. Nuclear Medicine: David Vállez García, Antoon Willemsen, Riemer Slart,

Gert Luurtsema, Philip Elsinga, Ronald Boelaard,

GMP laboratory

Nuclear Med technologists: Johan Wiegers, Eelco Severs, Paul van Snick,

Aafke Zeilstra, Yvonne van der Knaap

Dept. Neurology: Marcel Aries, Jan Willem Elting

Dept. Mathematics: Wim Krijnen

Dept. Radiology: Peter Jan van Laar

Dept. Neuropsychology: Fijanne Strijker

Dept. Epidemiology: Henk Groen

This study was financed by a grant from the Healthy Aging Pilot

Fund of the University Medical Center Groningen, The Netherlands

c.f.m.franssen@umcg.nl