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 5.33.9

3.0

5.43.5

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

Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University Critical Care 2014, 18:225

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 ModificationAnticoagulantion None or RegionalBlood flow Start slow and increase graduallyDialysate flow Flow 500 ml/min

≤ 10 mEq/L above serum sodiumBicarbonate 30 mEq/LHigh potassium and calcium if possible35 C temperature or isothermic

Dialyzer Avoid large surface areaDuration 2 hours initially then increase according to stabilityFrequency DailyOther 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

Healthcare

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