The Journal of Pediatrics
Volume 152, Issue 1 , Pages 4-6, January 2008

The Role of the Kidney in Protecting the Brain against Cerebral Edema and Neuronal Cell Swelling

  • Russell W. Chesney, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Russell W. Chesney, MD, Department of Pediatrics, University of Tennessee Health Science Center, 50 North Dunlap, Memphis, TN 38103.

Department of Pediatrics, University of Tennessee Health Science Center, Memphis, Tennessee

Article Outline

Abbreviations: ADH, Antidiuretic hormone, SIADH, Syndrome of inappropriate secretion of ADH, TonE, Tonicity responsive enhancer element, TonEBP, Tonicity enhancer binding protein

 

This year is the golden anniversary of the classic article defining the maintenance need for water in parenteral fluid therapy in children.1 The prescription of a hypotonic solution for hospitalized children has come under fire in recent publications.2, 3, 4 What is clear, regardless of the recommendation for maintenance fluid therapy, is that replacement of fluids lost during dehydration, burns, diarrhea, or vomiting should consist of isotonic sodium chloride (0.9%) or Ringer’s lactate solution. In dispute is whether isotonic sodium chloride should be used in place of 0.225% or 0.45% sodium chloride as maintenance fluid.1, 2, 3, 4 This commentary is not intended to further debate these opposing points of view, but rather to review the adaptive mechanisms by which the kidney and cell volume regulatory processes protect the brain against hyponatremia. The prescient statement of the late Dr. Norman Siegel—“The dumbest kidney is smarter than the smartest nephrologist”—is particularly relevant in topical overview (personal communication).

See related article, p 33

Although it is clear that hyponatremia can lead to cerebral edema, venous tearing, uncal herniation, and even death,2, 3, 5 these events are fortunately uncommon. In the current issue of the The Journal, Au et al6 indicate that even in postoperative patients, a group in which hyponatremia has been reported to be high, moderate hypernatremia is found in approximately 10% of these patients. To wit, millions of children have safely received hypotonic sodium chloride solutions as maintenance therapy. How is it that a child receiving such a solution is usually found to have serum sodium and chloride concentrations in the normal range? At least 5 simultaneously occurring physiological processes are at play: (1) factors that diminish antidiuretic hormone (ADH) secretion; (2) a reduced movement of certain aquaporins (water channels) into relevant cell membranes in the kidney and brain; (3) movement of ionic and nonionic osmolytes out of cells (especially in the brain); (4) regulatory maintenance of cell volume; and (5) an elaborate intracellular osmolar sensing system.7, 8, 9, 10, 11, 12, 13, 14, 15

ADH secretion is regulated by plasma osmolarity and vascular volume.5 Decreased effective circulatory volume (hypovolemia) increases ADH production and secretion.3, 5 In some hypervolemic states, including congestive heart failure, cirrhosis, and the nephrotic syndrome, the effective plasma volume is diminished, and ADH concentrations are high. Sodium retention is brisk, especially in these hypervolemic states; hence, isotonic sodium chloride may not be appropriate in congestive heart failure, cirrhosis, and nephritic syndrome. Importantly, however, some nonhemodynamic states can result in increased and persistent ADH secretion, which results in the syndrome of inappropriate secretion of ADH (SIADH),3 with reduced urinary water excretion and hyponatremia. This particular situation will be touched on later.

Usually, osmoreceptors (mainly in the brain) and volume receptors (often in the chest) sense osmoreduction and concomitant volume sufficiency leading to a decline in ADH synthesis and a fall in secretion of the hormone. Because ADH regulates the movement of kidney-pertinent aquaporins (aquaporins 1 to 4), less ADH results in a reduction in the number of water channels per collecting duct cell, and, hence, urine-concentrating capacity is diminished.5, 7, 14 The mechanism of aquaporin action in the collecting duct of distal tubules in the renal medulla is that an increase in the membrane population of water channels augments transepithelial water permeability and allows osmotic equilibrium of intraluminal and periluminal fluid. Additional evidence of the role of aquaporins in urinary concentration and dilution are the failure of formation of concentrated urine in knockout mice lacking certain aquaporins14 and the concentrating defect in certain patients with autosomal recessive nephrogenic diabetes insipidus.8 Under the condition of reduced aquaporin density in collecting duct cell plasma membranes, urinary concentrating ability is impaired and a water diuresis ensues. Thus, in the child receiving a hypotonic solution whose plasma ADH values fall, water excretion is brisk.

Aquaporins also act in other tissues, including the brain.16 Aquaporin 4 in particular is located at brain sites where water movement between the cerebrospinal fluid, blood, and intracellular and interstitial spaces occurs. Aquaporin 4–deficient mice show a greater degree of hydrocephalus in an obstructive hydrocephalus model as compared with normal mice rendered hydrocephalic. Furthermore, the knock-out mice are protected against hypernatremic brain swelling when hypernatremia is imposed, in comparison to control mice.16 Numerous studies are consistent with the idea that a reduction in water channel abundance influences both renal collecting duct and brain astrocyte water movement in response to hypotonic solutions given as maintenance parenteral therapy.

Both hypotonic and hypertonic stimuli also modify the movement of a group of ionic and non-ionic molecules, termed osmolytes, into or out of the cell.10, 12, 13 The predominant organic osmolytes are amino acids (taurine, betaine, glycine, alanine, and glutamate), polyalcohols (myoinositol and sorbitol) and creatine and glycerophosphorylcreatine.10 These molecules exist free in the cytosolic intracellular water and when faced with a hypoosmotic stimulus exit the cell. The osmolytes are usually accompanied by other ions, especially potassium and chloride.10, 13 Potassium and chloride can also exit via specific ion channels.

Under the condition of hypoosmolarity, rapid cell swelling occurs, which triggers an adaptive response (termed “cell volume regulation”) that maintains normal cell volume. Intracellular osmolytes are extruded, especially organic osmolytes, potassium, and chloride,10 and the swollen cell returns to normal. This response occurs within minutes.

The intracellular osmotic signaling processes that allow cell volume regulation are complex and involve the activity of chloride channels, stretch-activated potassium channel opening, and various integrins, growth factor receptors, and tyrosine kinases.10, 13 One remarkable osmosignaling factor is a tonicity enhancer binding protein (TonEBP), which in turn binds to a tonicity-responsive enhancer element (TonE) found in the promoter region of those genes important in osmotolerance.9 The genes regulated by TonE include aldose reductase (essential for the synthesis of sorbitol), and the transporters of taurine, betaine, and myoinositol.15 In regulating the intracellular content of these nonionic osmolytes, TonEBP controls the osmotic status of the cytosol. A remarkable biologic example of the TonE-TonEBP system is the enhancement of taurine, betaine, and myoinositol uptake that occurs in aquatic animal myocytes as freshwater fish proceed into brine, and enhancement of osmolyte egress when brine-tolerant fish reenter fresh water.11

Clinically, a child with one of the nonosmotic and nonvolumetric states of ADH excess or SIADH, such as meningitis or encephalitis, pneumonia, asthma, emesis, pain or stress, and certain medications (including cyclophosphamide, vincristine, or selective serotonin reuptake inhibitors), should be considered to be a risk for hyponatremia and its consequences. If given maintenance solutions that are hypotonic, such a child should have frequent measurement of electrolyte values.3

In conclusion, administration of hypotonic intravenous solutions for maintenance therapy in most children does not automatically result in overhydration, cell swelling, and a precipitous fall in serum sodium. The mechanisms herein described a reduction in ADH synthesis and secretion, diminished aquaporin density in relevant cell membranes, maintenance of cell volume regulation by the efflux of ionic and nonionic osmolytes and operation of the TonE-TonEBP system—all participate in a water diuresis and steady cell volume that prevents large swings in extracellular volume and extreme hyponatremia. Nonetheless, the careful physician needs to be aware of those clinical situations when SIADH may pertain.

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References 

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  12. Tsai TT, Guttapalli A, Agrawal A, Albert TJ, Shapiro IM, Risbud MV. MEK/ERK signaling controls osmoregulation of nucleus pulposus cells of the intervertebral disc by transactivation of TonEBP/OREBP. J Bone Miner Res. 2007;22:965–974
  13. Veizis IE, Cotton CU. Role of kidney chloride channels in health and disease. Pediatr Nephrol. 2007;22:770–777
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  15. Zhang Z, Ferraris JD, Brooks HL, Brisc I, Burg MB. Expression of osmotic stress-related genes in tissues of normal and hyposmotic rats. Am J Physiol Renal Physiol. 2003;285:F688–F693
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PII: S0022-3476(07)00969-9

doi:10.1016/j.jpeds.2007.10.009

Refers to article:

  • Incidence of Postoperative Hyponatremia and Complications in Critically-Ill Children Treated with Hypotonic and Normotonic Solutions , 23 November 2007

    Alicia K. Au, Patricio E. Ray, Kevin D. McBryde, Kurt D. Newman, Steven L. Weinstein, Michael J. Bell
    The Journal of Pediatrics January 2008 (Vol. 152, Issue 1, Pages 33-38)

The Journal of Pediatrics
Volume 152, Issue 1 , Pages 4-6, January 2008

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