Brain-kidney crosstalk: The Effect of Acute Kidney Injury on the Brain and Cerebral Function

Brain-kidney Crosstalk

The Effect of Acute Kidney Injury on the
Brain and Cerebral Function

Arkom Nongnuch, M.D.

Renal unit, Department of Medicine, Faculty of Medicine,
Ramathibodi Hospital, Mahidol University

Outline
AKI as systemic inﬂammatory condition

Effect of AKI on cerebral functions

Effect of AKI on drug metabolism

RRT in AKI and acute brain injury

Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
RIFLE VS AKIN
Critical Care 2009, 13:211

Median hospital length of stay (LOS) and organ failure
Clin J Am Soc Nephrol 1: 43-51, 2006

AKI as the risk of Death

Acute kidney injury is
not A cute kidney injury
Nephrol Dial Transplant (2008) 23: 1970︲1974
0
10
20
30
Risk (53.5 %) Injury (27.1 %) Failure (19.4 %)
26.0
12.9
5.1 5.3
3.9
3.0
5.4
3.5
2.3
ICU stays (days)
Total costs ( x 10000 $ )
Mortality (%)

Arkom Nongnuch, MD. Nephrology Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
AKI is Systemic condition
Interorgans crosstalk

Organs Crosstalk
The effects of one malfunctioning organ on the
function of another.

This effect is usually, but not necessarily,
detrimental to that organ and the whole organism.

Signals may be passed via neural, endocrine and
paracrine pathways, or (rarely) by direct cell–cell
signalling between organs

Blood Brain Barrier in AKI
Frontiers in Bioscience S4, 1375-1380, June 1, 2012
↑cytokine production

↓cytokine clearance
↑ROS
Accumulation of inﬂammatory cytokines in AKI lead to increase BBB permeability

AKI cause BBB disruption
Animal models of AKI have demonstrated disruption of the BBB with extravasation of albumin-
bound Evans blue dye compared with sham-operated controls) JASN 2008, 19:1360-1370

AKI crosstalk to brain
• Changes in cerebral neurotransmitters in AKI

• Changes in endocrine function in AKI

• Effect of inﬂammatory changes induced by AKI on the brain

• Acid-base disturbances in AKI

• Organic osmolytes and brain water changes in AKI

• Effect of AKI on organic ion transporters and drug
metabolism

AKI on brain via neurotransmitter
NEUROTRANSMITTERS are the brain chemicals that
communicate information throughout our brain and
body

Imbalance of neurotransmitter can cause cerebral
function abnormality ranging from impair motor
activity to coma

Most studies examine in animal model ( ischaemic
reperfusion injury, nephrectomy, ureteral ligation)

Neurotransmitter in AKI
↑ plasma norepinephrine, epinephrine and dopamine in
keeping with ↓ cerebral norepinephrine, epinephrine and
dopamine (Life Sci 1985, 37:1757–1764)

Dopamine turnover and
motor activity in AKI
The extent of the aMT-induced decrease in DA was suppressed in uremic rats in all regions
examined, suggesting a decrease in the DA turnover in uremia, involving impairment of motor activity

Intensive Care Med 2001, 27:1655–1660
Normal activity
↓Motor activity

AKI on brain via
hormonal disturbance
↑Catecolamines, vasopressin, natriuretic peptides
and the renin–angiotensin–aldosterone axis

Renal sympathetic nerve overactivity leading to
posterior reversible leukoencephalopathy

AKI cause cytokine accumulation
Ischemic renal injury leads to magniﬁed humeral
immune response in mice (J Am Soc Nephrol 24: 1063–1072,
2013)

!
Increase cytokines production and decrease
cytokines clearance in bilateral nephrectomised
rat (Nephrol Dial Transplant (2012) 27: 4339–4347)

AKI leading to increase
cytokine/chemokine
protein in the kidney
and the brain within
hour.
J Am Soc Nephrol. 2008 July ; 19(7): 1360-1370

AKI on brain via inﬂammatory cascade
J Am Soc Nephrol 2013, 24:529-536

J Am Soc Nephrol 2008, 19:1360–1370

3 Waves danger
signalling
glial ﬁbrillary acidic protein in the brain

AKI on brain via acid-base disturbance
Increasing intracellular acidification leads to an increasing affinity
of ammonia Km [NH4+] for human glutamate dehydrogenase, so
resulting in oxidative deamination of glutamate.

An increasingly intracellular acidic environment, protons can
activate acid-sensing ion channels – resulting in an influx of both
sodium and calcium into the cell, leading to cell membrane
depolarisation and cellular injury and cell death.

The reduction in pH in the cerebrospinal fluid has local
vasodilatory effects on the cerebral parenchymal arterioles.

AKI on brain via acid-base disturbance
Molecular Brain 2013, 6:1

AKI cause increase brain water
J Am Soc Nephrol 1993, 3:1913-1919
↓

Brain water and organic
osmolyte in AKI
Brain water (%)
Animal study revealed increase brain organic osmolyte in keeping with
maintaining brain water content in AKI, not ESRD.
J Am Soc Nephrol 1993, 3:1913-1919
↑
↑
↑
↑
↑
←→

Brain water in AKI and dialysis
J Am Soc Nephrol 1995, 6:1600-1606.
↓ ↑
Animal study showed decrease brain water in ureic AKI rats, however,
increase brain water in post rapid dialysis rats.

AKI on brain via organic
osmolyte and water
Clin J Am Soc Nephrol, In Press, Aug 2014.
Regulartory volume increase

Cell shrinkage
Regulartory volume decrease

Cell edema
AKI Dialysis

Transport protein in BBB
BioImpacts, 2012, 2(1), 5-22

AKI on brain via organic transporter
and drug metabolism
BioImpacts, 2012, 2(1), 5-22
P-gp
OATs

AKI on hepatic drug metabolism

AKI on CYP enzyme


Drug may accumulate in AKI

Mechanisms associated with cerebral
dysfunction during acute kidney injury

Mechanisms Results
Impaired Blood-brain barrier
integrity
Alteration of essential amino acid level, inﬂammatory mediators, organic
osmolyte in the brain
Neurotransmitter derangements Decrease cerebral norepinephrine, epinephrine, dopamine may leading to
impair locomotors activity
Endocrine disturbance Stimulation RAAS system and sympathetic nervous system leading to
hypertension
Trigger inﬂammatory cascade Three waves danger signaling unleashing uric acid, Weibel-Palade bodies
and HMGB1
Acid-base disturbance Activate acid-sensing ion channels (ASIC) leading to cellular injury

local vaso-dilatory effects as a results of cerebral oedema
Organic osmolyte and brain
water disturbances
Increase idiogenic osmole and reduction of brain water
Alteration of drug
pharmacokinetics
Down regulation of OATs and OCTs

Alteration of protein binding of drug

Impair renal and hepatic clearance of drug

Mechanisms associated with cerebral
dysfunction during acute kidney injury

RRT in AKI and acute brain
injury setting
Urea is rapidly removed from the plasma water
during intermittent haemodialysis, but there is a
delay in urea moving out of cells, leading to brain
swelling.

Rapid increase blood pH -> paradoxical intracellular
acidosis and suppress respiratory centre

Intradialytic hypotension may potentiate brain injury

Recommendations for
dialysis in acute brain injury
Dialysis script Modification
Anticoagulantion None or Regional
Blood flow Start slow and increase gradually
Dialysate flow Flow 500 ml/min
≤ 10 mEq/L above serum sodium
Bicarbonate 30 mEq/L
High potassium and calcium if possible
35 C temperature or isothermic
Dialyzer Avoid large surface area
Duration 2 hours initially then increase according to stability
Frequency Daily
Other Consider oxygen supplement
Hemodialysis International 2008; 12:307︲312

Take home messages
AKI is systemic inflammatory condition

Cerebral dysfunction in AKI owing to not only
uraemic toxin and imbalance of water ,acid base
as but also dysfunction of cytokines, transport
proteins and neurotransmitters.

Modification of dialysis prescriptions may alleviate
further cerebral damage such as slow blood flow,
short dialysis time, high dialysate Ca2+, Na+ and
low temperature

Thank you for your attention

Brain-kidney crosstalk: The Effect of Acute Kidney Injury on the Brain and Cerebral Function

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