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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 5.3
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
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 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
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

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

  • 1. 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
  • 2. 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
  • 3. Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University RIFLE VS AKIN Critical Care 2009, 13:211
  • 4. Median hospital length of stay (LOS) and organ failure Clin J Am Soc Nephrol 1: 43-51, 2006
  • 5. AKI as the risk of Death Critical Care 2009, 13:211
  • 6. 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 5.3 3.9 3.0 5.4 3.5 2.3 ICU stays (days) Total costs ( x 10000 $ ) Mortality (%)
  • 7. Arkom Nongnuch, MD. Nephrology Unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University AKI is Systemic condition Interorgans crosstalk
  • 8. 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
  • 9. 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
  • 10. 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
  • 11. 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
  • 12. 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)
  • 13. 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)
  • 14. 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
  • 15. 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
  • 16. 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)
  • 17. 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
  • 18. 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
  • 19. 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.
  • 20. 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
  • 21. 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 ↓
  • 22. 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 ↑ ↑ ↑ ↑ ↑ ←→
  • 23. 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.
  • 24. 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
  • 25. 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
  • 26. 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
  • 28. 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
  • 29. 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
  • 30. 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
  • 31. 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
  • 32. 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
  • 33. 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
  • 34. 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 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
  • 35. 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
  • 36. Arkom Nongnuch, M.D. Nephrology unit, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University Thank you for your attention