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The Effect of Acute Kidney Injury on the Brain and Cerebral Function
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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
Critical Care 2009, 13:211
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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)
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Neurotransmitter in AKI
↑ plasma norepinephrine, epinephrine and dopamine in keeping with ↓ cerebral norepinephrine, epinephrine and dopamine (Life Sci 1985, 37:1757–1764)
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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)
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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.
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
AKI on brain via acid-base disturbance
Molecular Brain 2013, 6:1
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
AKI cause increase brain water
J Am Soc Nephrol 1993, 3:1913-1919
↓
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
↑↑
↑↑
↑←→
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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.
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Transport protein in BBB
BioImpacts, 2012, 2(1), 5-22
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
AKI on brain via organic transporter and drug metabolism
BioImpacts, 2012, 2(1), 5-22
P-gp OATs
Critical Care 2014, 18:225
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
AKI on hepatic drug metabolism
Critical Care 2008, 12:235
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
AKI on CYP enzyme
\
Critical Care 2008, 12:235
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Drug may accumulate in AKI
Critical Care 2008, 12:235
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
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
Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University
Thank you for your attention