Intensive Care Med (2019) 45:1112–1115

https://doi.org/10.1007/s00134-019-05685-z

UNDERSTANDING THE DISEASE

Understanding the renal response to brain

injury
Matthieu Legrand1,2,3*  and Romain Sonneville3,4

© 2019 Springer-Verlag GmbH Germany, part of Springer Nature

Introduction vasopressors’ infusion. Pressure-induced natriuresis is

Acute brain injury induces changes to remote organs, aimed at lowering intravascular blood volume and blood
including the kidney. We briefly review acute brain pressure through natriuresis when arterial pressure rises
injury-associated changes in renal function and how they [5]. Since it represents a physiological response to sys-
impact treatments. temic hemodynamic changes, a more appropriate term of
“renal salt wasting” was proposed [6].
1. Water and sodium handling.
What are the therapeutic implications?
Both in SIADH and CSWS, fluid management should be
Hyponatremia adjusted based on urine osmolarity [2]. Infusing hypo- or
Rapid development of hypo-osmolar hyponatremia isotonic solutes (i.e., with osmolarity lower than urine)
(natremia < 135  mmol/L) can generate cerebral edema, leads to free-water retention and promotes hyponatremia
seizures, increase intracranial pressure (ICP), and (Fig.  1). This phenomenon is described as desalination
increase the risk of cerebral ischemia [1]. [7], where infused sodium and chloride are excreted
Hyponatremia is the consequence of increased renal as osmoles while sodium-free water is reabsorbed due
free-water reabsorption after antidiuretic hormone to the action of ADH at the collector tube level (Fig. 1).
(ADH) secretion [2]. Two mechanisms of excessive ADH Infusion of normal saline will result in positive free-
secretion have classically been proposed in neuro-ICU water balance, despite having slightly higher osmolarity
patients: the syndrome of inappropriate ADH secretion compared to plasma, and promote hyponatremia in the
(SIADH) and the cerebral salt-wasting syndrome (CSWS) context of high ADH and high urine osmolarity. Restric-
(online supplemental material, Table  1). Under normal tion of sodium-free water administration and admin-
physiological circumstances, ADH secretion is inhibited istration of hypertonic saline is expected to prevent or
when plasma osmolarity drops. In the so-called SIADH, correct hyponatremia both in SIADH and CSWS, and
ADH secretion will increase despite hyponatremia [3]. should be considered as the first-line strategy. Oral urea
In CSWS, decreased vascular volume resulting from administration (15–30  g daily) is an alternative effective
high natriuresis and negative sodium balance is the trig- strategy to correct hyponatremia in SIADH that can be
ger for ADH secretion. Potential mechanisms of CSWS considered in less-severe patients or as a second-line
include release of natriuretic peptides [4] and “pressure- treament [8]. Urea only partially crosses the brain capil-
induced natriuresis” secondary to increased systemic laries, maintaining a plasma-to-brain concentration gra-
arterial pressure after sympathic system activation or dient, decreasing brain-water content and ICP. However,
osmotic diuresis secondly occurs with loss of electrolyte-
free water leading to a rise of serum sodium concentra-
*Correspondence: matthieu.m.legrand@gmail.com tion (i.e., the lower the urine osmolarity, the higher the
1
AP‑HP, GH St‑Louis‑Lariboisière, Department of Anesthesiology loss of electrolyte-free water and rise of serum sodium)
and Critical Care and Burn Unit, St-Louis Hospital, Assistance Publique- making it inappropriate in CSWS.
Hôpitaux de Paris, Paris, France
Full author information is available at the end of the article Correction of hypovolemia is required in CSWS,
making hypertonic saline the best choice, for the
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Fig. 1  Impact of perfusion of normal saline versus hypertonic saline on free-water balance and natremia changes in the setting of high antidiuretic
hormone (ADH) secretion. Left panel: ADH is a stress hormone secreted by hypothalamic neurons in response to brain injury and low intravascular
volume. In the context of brain injury, excessive ADH secretion due to SIADH or CSWS will result in high urine osmolarity and renal electrolyte-free
water reabsorption while the kidney excretes osmoles (i.e., electrolytes). Infusion of NaCl 0.9% despite having slighter higher osmolarity compared
to plasma, will result in positive free-water balance and promote hyponatremia in this context (1). In the example depicted with urine osmolar-
ity ≈ 600 mOsmol/L due to high ADH secretion, administration of osmoles in normal saline (NaCl 0.9%, solute osmolarity ≈ 300 mosml/L) will be
eliminated in hyperosmolar urines (2), resulting in a net free-water positive balance, promoting hyponatremia (3). Right B: infusion of hypertonic
saline (4) (i.e., with osmolarity being superior to urine osmolarity) will result in increase of natremia, due to a negative free-water balance (5)

above-mentioned reasons. Adjusting arterial pressure consequence of decreased ADH secretion (i.e., diabe-
on cerebral blood flow autoregulation might further tes insipidus after pituitary surgery and in brain-dead
help tailoring arterial pressure level and avoid unneces- patients) [12].
sary and potentially harmful systemic hypertension [9].
Finally, administration of hydrocortisone was shown to What are the therapeutic implications?
effectively decrease renal sodium excretion in patients Acute hypernatremia is sometimes induced as a thera-
with subarachnoid hemorrhage and CSWS [10]. In a ran- peutic target to reduce the ICP. Whether such prophy-
domized trial conducted in patients with CSWS compli- lactic hypertonic saline infusions are an effective and safe
cating meningitis, fludrocortisone, in addition to normal strategy to reduce ICP and improve outcomes is uncer-
saline and oral salt supplementation, resulted in earlier tain, and is currently being tested in a randomized con-
correction of hyponatremia but did not affect outcomes trolled trial (NCT03143751). Hypernatremia induced by
[11]. mannitol might be less predictable due to variable renal
free-water losses. Titration of mannitol adjusted on renal
Hypernatremia response (i.e., diuresis) and plasma osmol gap is war-
Main causes of hypernatremia include infusion of hyper- ranted to limit the risk of secondary hypovolemia. The
tonic sodium solutions, free-water renal losses due to best strategy to prevent or correct excessive hyperna-
osmotic diuresis after mannitol infusion, loop diuret- tremia associated with mannitol is probably to monitor
ics administration, insufficient water intake, and extra- the osmol gap and decrease or stop mannitol if necessary.
renal losses. Excessive renal free-water loss may be the Excessive hypernatremia can also be corrected slowly by
1114

the administration of free water [13]; although this strat- Author details
1
 AP‑HP, GH St‑Louis‑Lariboisière, Department of Anesthesiology and Critical
egy has a risk on rebound intracranial hypertension. In Care and Burn Unit, St-Louis Hospital, Assistance Publique-Hôpitaux de Paris,
patients with diabetes insipidus, hypo-osmolar urine Paris, France. 2 F-CRIN INICRCT Network, Nancy, France. 3 Department of Inten-
output (i.e., < 100 mosmol/L) guides free-water (e.g., glu- sive Care Medicine and Infectious Diseases, Bichat-Claude Bernard University
Hospital, AP-HP, Paris, France. 4 UMR1148, LVTS, Sorbonne Paris Cité, Inserm/
cose 2.5% solution) volume supplementation adjusted on Paris Diderot University, Paris, France.
urine volume, and trigger recombinant antidiuretic hor-
mone supplementation. Acknowledgements
We thank Pr Jean-Philippe Haymann for his critical review of the manuscript.

2. Changes in renal glomerular function. Compliance with ethical standards

Conflicts of interest
ML received grants from the French Ministry of Health, research support from
Glomerular hyperfiltration Sphingotec, lecture fees from Baxter and Fresenius, and consulting fees from
Hyperfiltration is diagnosed after identification of high Novartis, all outside the submitted work. RS received grants from the French
Ministry of Health, from the French society of intensive care medicine (SRLF),
creatinine clearance (i.e., CreatCl > 120 ml/min) using the from the European society of intensive care medicine (ESICM), and lecture fees
following equation: CreatCl = [urine creatinine × (urine from Baxter.
volume/serum creatinine)/minutes of urine collection].
Ethical approval
Increased cardiac output and high arterial pressure are This article does not contain any studies with human participants or animals
associated with augmented renal clearance at the early performed by any of the authors.
phase of acute brain injury [14].
Publisher’s Note
What are the therapeutic implications? Springer Nature remains neutral with regard to jurisdictional claims in pub-
lished maps and institutional affiliations.
Renal hyperfiltration exposes to therapeutic underdosing
of drugs with renal elimination (i.e., antibiotics, anti-epi- Received: 18 May 2019 Accepted: 2 July 2019
leptic drugs) and drug-level monitoring and adjustment Published online: 11 July 2019
should be considered [15].

Acute kidney injury References

Acute kidney injury (AKI) occurs in up to 20% of acute 1. Citerio G, Gaini SM, Tomei G, Stocchetti N (2007) Management of 350
brain injury patients and is associated with higher mor- aneurysmal subarachnoid hemorrhages in 22 Italian neurosurgical cent-
ers. Intensive Care Med 33:1580–1586. https​://doi.org/10.1007/s0013​
tality. Chronic kidney disease, use of nephrotoxic agents, 4-007-0700-5
hyperchloremia, rhabdomyolysis, and sepsis were identi- 2. Spasovski G, Vanholder R, Allolio B et al (2014) Clinical practice guideline
fied as risk factors. Brain death induces systemic immune on diagnosis and treatment of hyponatraemia. Nephrol Dial Transplant
Off Publ Eur Dial Transpl Assoc—Eur Ren Assoc 29(Suppl 2):i1–i39. https​
response, neurohormonal activation, endothelial activa- ://doi.org/10.1093/ndt/gfu04​0
tion and hemodynamic instability, all potential contribut- 3. Szmydynger-Chodobska J, Zink BJ, Chodobski A (2011) Multiple sites of
ing factors to kidney injury and delayed allograft function vasopressin synthesis in the injured brain. J Cereb Blood Flow Metab Off J
Int Soc Cereb Blood Flow Metab 31:47–51. https​://doi.org/10.1038/jcbfm​
[16]. .2010.188
4. Berendes E, Walter M, Cullen P et al (1997) Secretion of brain natriuretic
What are the therapeutic implications? peptide in patients with aneurysmal subarachnoid haemorrhage. Lancet
Lond Engl 349:245–249
The risk of AKI should be assessed when using poten- 5. Ivy JR, Bailey MA (2014) Pressure natriuresis and the renal control of
tial nephrotoxic drugs and requires creatinine and urine arterial blood pressure. J Physiol 592:3955–3967. https​://doi.org/10.1113/
output monitoring. Fluid balance should be carefully jphys​iol.2014.27167​6
6. Maesaka JK, Imbriano LJ, Ali NM, Ilamathi E (2009) Is it cerebral or renal
adjusted, as both hypovolemia and venous congestion salt wasting? Kidney Int 76:934–938. https​://doi.org/10.1038/ki.2009.263
were identified as risk factors for brain and kidney inju- 7. Steele A, Gowrishankar M, Abrahamson S et al (1997) Postoperative
ries [17, 18]. Specifically, prevention and correction of hyponatremia despite near-isotonic saline infusion: a phenomenon of
desalination. Ann Intern Med 126:20–25
hypovolemia (e.g., after mannitol infusion) are expected 8. Decaux G, Andres C, Gankam Kengne F, Soupart A (2010) Treatment of
to limit the risk of AKI [19]. euvolemic hyponatremia in the intensive care unit by urea. Crit Care
To conclude, monitoring of free-water handling and Lond Engl 14:R184. https​://doi.org/10.1186/cc929​2
9. Klein SP, Depreitere B, Meyfroidt G (2019) How I monitor cerebral
glomerular filtration allows therapeutic adjustments autoregulation. Crit Care Lond Engl 23:160. https​://doi.org/10.1186/s1305​
through understanding of the renal physiology after 4-019-2454-1
acute brain injury. 10. Katayama Y, Haraoka J, Hirabayashi H et al (2007) A randomized con-
trolled trial of hydrocortisone against hyponatremia in patients with
Electronic supplementary material aneurysmal subarachnoid hemorrhage. Stroke 38:2373–2375. https​://doi.
The online version of this article (https​://doi.org/10.1007/s0013​4-019-05685​-z) org/10.1161/STROK​EAHA.106.48003​8
contains supplementary material, which is available to authorized users.
 1115

11. Misra UK, Kalita J, Kumar M (2018) Safety and efficacy of fludrocortisone 16. Civiletti F, Assenzio B, Mazzeo AT et al (2019) Acute tubular injury is asso-
in the treatment of cerebral salt wasting in patients with tuberculous ciated with severe traumatic brain injury: in vitro study on human tubular
meningitis: a randomized clinical trial. JAMA Neurol 75:1383–1391. https​ epithelial cells. Sci Rep 9:6090. https​://doi.org/10.1038/s4159​8-019-42147​
://doi.org/10.1001/jaman​eurol​.2018.2178 -4
12. Nongnuch A, Panorchan K, Davenport A (2014) Brain-kidney crosstalk. 17. Ameloot K, Genbrugge C, Meex I et al (2016) Is venous congestion
Crit Care Lond Engl 18:225. https​://doi.org/10.1186/cc139​07 associated with reduced cerebral oxygenation and worse neurological
13. Chauhan K, Pattharanitima P, Patel N et al (2019) Rate of correction of outcome after cardiac arrest? Crit Care Lond Engl 20:146. https​://doi.
hypernatremia and health outcomes in critically Ill patients. Clin J Am Soc org/10.1186/s1305​4-016-1297-2
Nephrol CJASN 14:656–663. https​://doi.org/10.2215/CJN.10640​918 18. Legrand M, Dupuis C, Simon C et al (2013) Association between systemic
14. Udy A, Boots R, Senthuran S et al (2010) Augmented creatinine clearance hemodynamics and septic acute kidney injury in critically ill patients: a
in traumatic brain injury. Anesth Analg 111:1505–1510. https​://doi. retrospective observational study. Crit Care Lond Engl 17:R278. https​://
org/10.1213/ANE.0b013​e3181​f7107​d doi.org/10.1186/cc131​33
15. Carrie C, Bentejac M, Cottenceau V et al (2018) Association between 19. Oddo M, Poole D, Helbok R et al (2018) Fluid therapy in neurointensive
augmented renal clearance and clinical failure of antibiotic treatment in care patients: ESICM consensus and clinical practice recommenda-
brain-injured patients with ventilator-acquired pneumonia: a preliminary tions. Intensive Care Med 44:449–463. https​://doi.org/10.1007/s0013​
study. Anaesth Crit Care Pain Med 37:35–41. https​://doi.org/10.1016/j. 4-018-5086-z
accpm​.2017.06.006