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Susceptibility to hyponatremia in the elderly: causes and consequences
Frenkel, Nanne
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Frenkel, W. J. (2014). Susceptibility to hyponatremia in the elderly: causes and consequences
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Download date: 19 Jun 2017
Chapter 1
General introduction
and aim of this thesis
GENERAL INTRODUCTION
The world population is ageing due to better life expectancy1. In the Netherlands, the
life expectancy for men increased from 70 years in 1950 to 79 in 2012 and for women from
73 years to 83 years2. With an increased life expectancy, a growing risk of chronic diseases,
comorbidities, hospitalization, institutionalization and mortality can be expected1,3,4.
Especially elderly are at risk and in this group of patients, acute medical illness is often
followed by progressive functional decline, whereas younger patients usually display a
higher chance to recover from illness without permanent injury. As a consequence, acute
medical illness in the elderly results in increased rates of hospitalization and re-admission,
institutionalization and mortality5,6. In this regard and in the light of increasing health cost
expenditure, adequate assessment of high risk subjects in the ageing population should
be useful for optimizing treatment and individual decision-making. In particular, prediction
models to determine prognosis might become pivotal to identify the high-risk elderly
patient. This thesis explores how disturbances in water homeostasis contribute to morbidity
and mortality in elderly subjects and tries to unravel some of the pathophysiological
mechanisms underneath.
Regulation of water homeostasis
From an evolutionary perspective maintaining water homeostasis is vital for all
living organisms. In the human body, the water balance is maintained by water intake
and excretion. Water balance deviations are reflected as changes in plasma osmolality.
Under normal physiological circumstances, plasma osmolality is principally determined
by plasma sodium. Thus, changes in the plasma sodium concentration reflect changes in
osmolality. In case of water excess, plasma sodium concentration is low (hyponatremia)
resulting in a hypo-osmotic state. Vice versa, relative shortage of water results in an increase
in plasma sodium levels (hypernatremia), reflecting a hyperosmotic state. The human body
is able to regulate water flux by specific water channels, also known as aquaporins, whereas
sodium homeostasis is regulated by specific sodium pumps. In addition, water and volume
homeostasis is regulated by osmo- and volume sensing receptors in the brain and the
kidney.
Together these mechanisms maintain plasma sodium concentration within very narrow
limits with a variation <3.5% from the normal distribution 7. In states of hypernatremia or
hypovolemia, central osmoreceptors and arterial baroreceptors sense the change in plasma
osmolality and volume, respectively, leading to thirst and the release of the antidiuretic
hormone arginine-vasopressin. Small changes in plasma osmolality by 1-2% are detected
by osmoreceptors located in the circumventricular organs of the hypothalamus8,9. Activated
osmosensitive neurons will guide their action potentials to the thirst sensation region, and to
the magnocellular neurons of the supraoptic nucleus (SON), which produce vasopressin10,11.
These neurons project to the posterior pituitary where they release vasopressin into the
– 10 –
bloodstream upon activation. Released vasopressin subsequently flows to the renal
collecting duct principal cells where it will bind the vasopressin 2 receptor (V2R). Here,
a cAMP-mediated signaling cascade is initiated which ultimately leads to an increase in
aquaporin (AQP)-2 protein expression in the apical membrane resulting in increased water
reabsorption and correction of the hypernatremia or hypovolemia 12. Upon correction,
vasopressin release is reduced and a steady state plasma osmolality is re-established.
Ageing and the susceptibility to hyponatremia
It has been widely recognized that with ageing the susceptibility to alterations in water
balance increases. Although the propensity for both hyper- and hyponatremia increases,
the prevalence of hyponatremia (and related complications) is much higher than the risk
of hypernatremia in elderly populations13. The increased susceptibility to hyponatremia in
elderly individuals involves several age-related physiological changes, which in conjunction
with use of medication or intercurrent illness, may lead to clinically relevant and, sometimes,
life threatening hyponatremia14,15. One of the examples linking increased susceptibility to
hyponatremia to physiological changes in the body that is getting older is the change
in total body water (TBW). TBW decreases with age mainly because of a reduction in
intracellular water secondary to loss of muscle mass and a relative increase in fat mass.
Consequently, the extracellular water compartment respective to intracellular water increases
in elderly subjects and the ability to correct changes in osmolality decreases due to relative
extracellular water excess 16. In general, the various physiological and pathophysiological
factors that contribute to age-related increase in the propensity for hyponatremia can be
divided in changes in renal water excretion, central osmoregulation, and extra-renal water
loss, respectively.
1. Age-related changes in renal water excretion
The ability for the kidneys to excrete water is diminished in elderly individuals, resulting
in a decreased ability to excrete a water load16,17. The reason for the diminished water
excretory capacity seems to involve both diminished free water excretion (defined as the
amount of excreted free water that is excreted by the kidneys without solutes), and reduced
solute-mediated water excretion (i.e., the amount of water which is excreted by the kidneys
as a result of solute excretion). The impairment of free water excretion with age seems to
be dependent on a reduction in renal plasma flow and a decline in glomerular filtration
rate (GFR). By inducing a reduction in net delivery of fluids to the loop of Henle due to a
lower GFR, responsible for sodium and water reabsorption, the diluting and concentrating
ability of the kidneys will diminish. The sequelae of a lower renal plasma flow - inducing a
lower flow to the medulla, consequently leading to a lower medullary osmotic gradient,
while the net solute excretion per nephron is increased when GFR is decreased – will also
lead to a decreased diluting capacity of the collecting duct, thus enhancing the impairment
in free water excretion6,18.
– 11 –
General introduction
1
Also, age-related decrease in the production of renal prostaglandins seems to
influence the capacity to excrete water. Decreased prostaglandin levels will impair free
water by inducing a diminished renal plasma flow, in concert with both reduction in GFR
and agonizing the antidiuretic effect of vasopressin20. In addition, considering that the
amount of solutes needed to be excreted is an important factor for urine production, lower
intake of solutes, as frequently seen in elderly subjects, importantly affects solute-mediated
water excretion. Together with the urinary excretion of sodium potassium and chloride,
urea, the major end product of nitrogen metabolism, affects urine concentrating ability. A
decreased urea, as a result of a low protein intake may contribute to decreased medullary
concentrating ability and, consequently, to reduced solute-mediated water excretion 21,22.
The decrease in urea production with ageing is likely caused by both a decrease in protein
intake and a reduction in muscle mass, which is an important generator of endogenous
protein catabolism and urea excretion23.
2. Age-related changes in central osmoregulation
Levels of thirst and ad libitum drinking, in response to increased osmolality or a
decreased circulation volume, decrease with advancing age, making older people more
vulnerable to disturbances in water homeostasis24. Observational studies show that during
life plasma vasopressin concentration rises progressively and that the secretory response
of vasopressin to plasma hypertonicity and plasma volume reduction is enhanced25-27. Next
to osmoreceptor hypersensitivity, changes in age-related volume- and pressure-mediated
vasopressin release are proposed as possible mechanism to the exaggerated vasopressin
response in elderly28. Both human and animal studies suggest that age-related delay in the
sensory response of the osmoreceptors located in the oropharyngeal region contribute
to slowed suppression of vasopressin release when the osmolality level has already been
restored to normal. These changes in vasopressin release may be responsible for and
increased propensity to develop hyponatremia29.
3. Age-related changes in extra-renal water loss
In elderly individuals insensible water loss is diminished as a result of a more sedentary
lifestyle and reduced sweating capacity, which may contribute to disturbances in the water
balance 30. In everyday life, the production of hypo-osmotic sweat can be up to 10-12L a
day, with a sodium concentration up to 70 mmol/L, and is highly variable, depending on
e.g. environmental conditions and exercise31. Therefore, sweating provides an extra-renal
defense mechanism against hyponatremia that is lost with increasing age.
Patient-related factors associated with susceptibility to hyponatremia
Apart from the age-related pathophysiological factors as described above, the
tendency to develop hyponatremia in the elderly can be amplified by patient-related
factors such as comorbidity and drug use contributing to a hypo-osmotic state. Comorbid
– 12 –
conditions that are frequently observed in elderly subjects and affect vasopressin release are
gastrointestinal loss due to vomiting or diarrhea, heart failure and liver failure. In these cases,
hyponatremia is often seen as a result of reduced effective circulating volume leading to
vasopressin release and consequently water retention. In patients with advanced renal failure
the impairment of free water excretion can lead to water retention and the development
of hyponatremia, despite appropriate suppression of ADH32. In addition, conditions
that lead to autonomous production of vasopressin, i.e. the syndrome of inappropriate
antidiuretic hormone secretion (SIADH), principally resulting from diseases that affect the
brain or the lung are more common with advanced age. Besides comorbid conditions
affecting water homeostasis, drug and drug combinations that are known to stimulate
vasopressin release are frequently prescribed in elderly patients, including antidepressants,
antipsychotics, anticonvulsants and drugs used to treat Parkinson’s disease33. In addition,
thiazide diuretics are a well-known cause of hyponatremia in elderly patients, although the
underlying pathophysiological mechanism by which they elicit hyponatremia is still not
fully elucidated34. Proposed mechanisms include: 1. reset of the vasopressin affinity to the
vasopressin-receptor (AVPR2); 2. increased expression of AQP2 in the apical membrane of
the collecting duct; 3. angiotensin II-mediated stimulation of vasopressin and 4. increased
excretion of solutes in excess of water.
Sodium regulation with age
Renal sodium excretion is controlled by intrinsic renal mechanisms including the reninangiotensin aldosterone system and atrial natriuretic factor (ANF). The kidneys are capable
of excreting large amounts of sodium during states of sodium overload. With aging, the
ability of the kidney to respond to changes in plasma sodium diminishes. The half-time for
reduction of urinary sodium after salt restriction almost doubles in elderly patients35. The
sodium-losing tendency of the aging kidney is due to nephron loss that leads to increased
osmotic load per nephron and results in mild osmotic diuresis. In addition, reductions in
renin, angiotensin and aldosterone levels and increasing levels of ANF will further promote
urinary sodium loss13,26. Usually these age-related changes in sodium homeostasis will not
independently lead to disturbances in plasma sodium and osmolality, but may lead to a
hypo-osmotic state in the presence of impaired free water excretion for example by drugs
that stimulate vasopressin release or further promote renal sodium loss, such as reninangiotensin system blockers and diuretics.
AIM OF THIS THESIS
This thesis is the result of our observation that hyponatremia as evidence of disturbed
water and salt handling is frequently observed in acutely hospitalized elderly patients; while
in a normal healthy elderly population abnormalities in plasma sodium concentration are
– 13 –
General introduction
1
Figure 1. Age-related changes leading to hypo-osmolic state
uncommon. Based on the age-related physiological and pathophysiological changes that
occur with aging, as outlined above, we hypothesized that loss of integrity of water and salt
homeostasis, as evidenced by the presence of hypo- or hypernatremia is associated with an
adverse outcome in elderly patients. In order to address this issue, our aim was to assess
whether hypo- and hypernatremia could act as an independent predictor of mortality in
acutely hospitalized elderly patients (Chapter 4). To appropriately correct for co-morbidity
and physiological alterations in renal function associated with ageing, we first assessed
the validity of two important predictors of mortality in the elderly, notably the Charlson
Comorbidity index37 (Chapter 2) and the MDRD formula for the estimation of renal function
(Chapter 3) in this population. To gain further insight in the pathophysiological mechanism
of age-related hyponatremia, we studied the origin of hyponatremia associated with thiazide
diuretics (Chapter 5). Thiazide-induced hyponatremia is a condition almost exclusively
observed in elderly patients and the most common complication of thiazide diuretics
associated hospital admission. Although the working mechanism of thiazide diuretics is well
established, there is a time-honored debate about the potential mechanisms of thiazide– 14 –
induced hyponatremia. A previous study showed that thiazide-induced hyponatremia
is reproducible 38, thereby providing a model to study age-related susceptibility to
hyponatremia. Finally, we compared the effects of thiazide-type and thiazide-like diuretics
on cardiovascular outcome and mortality (Chapter 6). Thiazide-like diuretics have a
longer half-life and superior blood pressure lowering action compared to thiazide-like
diuretics39,40. However, thiazide-like diuretics such as chlorthalidone are associated with a
higher incidence of adverse effects, particularly hyponatremia41,21. Whether the potential
benefit of thiazide-like diuretics on blood pressure outweigh the detrimental effects on water
and salt homeostasis remains to be determined. We used a meta-analysis to compare the
effects of thiazide-type and thiazide-like diuretics on mortality and cardiovascular events.
In addition, we separately analyzed the possible disparate occurrence of adverse effects
associated with thiazide-like and thiazide-type diuretics.
– 15 –
General introduction
1
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General introduction