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Mekanisme Kelainan

The negative fluid balance that causes dehydration results from decreased intake, increased
output (renal, gastrointestinal [GI], or insensible losses), or fluid shift (ascites, effusions, and
capillary leak states such as burns and sepsis). The decrease in total body water causes
reductions in both the intracellular and extracellular fluid volumes. Clinical manifestations of
dehydration are most closely related to intravascular volume depletion. As dehydration
progresses, hypovolemic shock ultimately ensues, resulting in end organ failure and death.
Young children are more susceptible to dehydration due to larger body water content, renal
immaturity, and inability to meet their own needs independently. Older children show signs
of dehydration sooner than infants due to lower levels of extracellular fluid (ECF).
Dehydration can be categorized according to osmolarity and severity. Serum sodium is a
good surrogate marker of osmolarity assuming the patient has a normal serum glucose.
(Osmolarity = [2 × sodium] + [glucose/18] + [blood urea nitrogen/2.8]) Dehydration may be
isonatremic (130-150 mEq/L), hyponatremic (< 130 mEq/L), or hypernatremic (>150
mEq/L). Isonatremic dehydration is the most common (80%). Hypernatremic and
hyponatremic dehydration each comprise 5-10% of cases. Variations in serum sodium reflect
the composition of the fluids lost and have different pathophysiologic effects, as follows:
 Isonatremic (isotonic) dehydration occurs when the lost fluid is similar in sodium
concentration to the blood. Sodium and water losses are of the same relative
magnitude in both the intravascular and extravascular fluid compartments.
 Hyponatremic (hypotonic) dehydration occurs when the lost fluid contains more
sodium than the blood (loss of hypertonic fluid). Relatively more sodium than water is
lost. Because the serum sodium is low, intravascular water shifts to the extravascular
space, exaggerating intravascular volume depletion for a given amount of total body
water loss.
 Hypernatremic (hypertonic) dehydration occurs when the lost fluid contains less
sodium than the blood (loss of hypotonic fluid). Relatively less sodium than water is
lost. Because the serum sodium is high, extravascular water shifts to the intravascular
space, minimizing intravascular volume depletion for a given amount of total body
water loss.
Neurologic complications can occur in hyponatremic and hypernatremic states. Severe
hyponatremia may lead to intractable seizures, whereas rapid correction of chronic
hyponatremia (>2 mEq/L/h) has been associated with central pontine myelinolysis. During
hypernatremic dehydration, water is osmotically pulled from cells into the extracellular
space. To compensate, cells can generate osmotically active particles (idiogenic osmoles) that
pull water back into the cell and maintain cellular fluid volume. During rapid rehydration of
hypernatremia, the increased osmotic activity of these cells can result in a large influx of
water, causing cellular swelling and rupture; cerebral edema is the most devastating
consequence. Slow rehydration over 48 hours generally minimizes this risk (not to exceed 0.5
mEq/L per hour; 10-12 mEq/L in 24 hours).

Edema Mecanism
The fluid levels in the body are tightly regulated through homeostatic mechanisms involving
the kidneys and other parts of the body.
The production of interstitial fluid is regulated by the Starling equation forces. Hydrostatic
pressure building up within the blood vessels causes water to flow out of the blood vessels
and into the surrounding tissue. This increases the concentration of protein in the plasma,
which causes more fluid to be drawn back into the vessels from the tissue.
According to the Starling equation, the rate at which fluid flows to and from the blood vessel
walls depends on two important factors – the filtering forces and the permeability of the
vessel wall to water.
The majority of leakage occurs in the capillaries or post capillary venules, which have
membranes that are semipermeable and therefore allow water to pass more easily than
protein. Gaps between the cells of the vessel wall open up and the permeability to water is
increased. As the gaps increase in size, however, the membrane also becomes permeable to
protein. If the forces in the Starling equation are altered, edema is more likely to occur.
Factors that contribute to the development of edema include:
 An increase in the hydrostatic pressure
 A decrease in the blood vessel oncotic pressure
 An increase in tissue oncotic pressure
 An increase in vessel wall permeability.
 Obstructed lymphatic drainage
 Water retention in tissues.
Pathophisiology Hyponatremia
Hyponatremia can result from improper collection of a blood sample from a vein that is being
infused with hypotonic medications. Additionally, if older techniques (e.g., flame photometry
using whole plasma) for sodium measurement are being used, high levels of protein or
triglyceride in the sample can cause the sodium concentration to be falsely low
(pseudohyponatremia).4 Hyperglycemia can also cause hyponatremia, via osmotically
induced water movement from cells into the blood (translocational hyponatremia), resulting
in a relative decrease in serum sodium concentration in the absence of hypo-osmolality. The
sodium concentration should be increased by approximately 1.6 to 2 mmol/L for each 100-
mg/dL increase in glucose concentration above 100 mg/dL.4
Excess water intake is a rare cause of hyponatremia. In persons with preserved renal function,
any extra water intake above obligatory water loss is usually excreted in a dilute urine,
hyponatremia does not develop. However, in psychogenic polydipsia, ingesting large
volumes (>15-20 L/day) of water can result in hyponatremia, despite preserved renal function
and diluting ability.
However, most cases of hyponatremia are caused by decreased renal excretion of water,
secondary to persistent action of ADH or the use of medications that interfere with urinary
dilution (e.g., thiazide diuretics and nonsteroidal anti-inflammatory drugs [NSAIDs]). Most
of these clinical disorders (e.g., congestive heart failure, nephrotic syndrome, cirrhosis) share
a reduction in effective arterial blood volume, resulting in persistent ADH activity despite
hypo-osmolar plasma. In addition, acute or chronic renal failure results in reduced functional
nephron mass, decreased glomerular filtration rate, and therefore decreased capacity for water
The drugs most commonly associated with the development of hyponatremia are thiazide
diuretics and NSAIDs. The mechanism of diuretic-induced hyponatremia is complex and
includes interference with urinary dilution by the thick ascending loop of Henle and the distal
convoluted tubule, as well as volume contraction–induced increase in ADH secretion.
Hyponatremia occurs almost exclusively with thiazide diuretics because of preservation in
medullary osmolality and urine-concentrating ability. NSAIDs can lead to hyponatremia via a
decrease in prostaglandin-mediated suppression of ADH. Many other drugs can be associated
with hyponatremia via the augmentation of ADH release or action
Hyponatremia can also be seen in hypovolemic disorders where solute and water losses (e.g.,
diarrhea) result in hemodynamically mediated ADH release. Importantly, hyponatremia
results only if these losses are replaced with a source of free water (e.g., hypotonic fluids).
Other, less-common causes of hyponatremia include a reset osmostat, adrenal insufficiency,
hypothyroidism, low dietary solute intake, beer drinker’s potomania, and salt-wasting
nephropathy. Although the mechanisms of hyponatremia associated with adrenal or thyroid
dysfunction are complex and not entirely clear, replacement of the deficient hormone usually
leads to resolution of the hyponatremia, barring any other concomitant cause.

Pathophisiology Hypernatremia
An increase in serum sodium concentration is almost always a reflection of water loss rather
than sodium gain. Water loss results in the development of plasma hyperosmolality; via
hypothalamic sensors, this acts as a stimulant to thirst and production of ADH. Ultimately,
free water is ingested and reclaimed via the kidneys, and sodium concentration and
osmolality are restored to normal. Thus, the maintenance of hypernatremia requires
diminished thirst sensation or decreased access to water. Even in states of impaired ADH
release or reduced ADH function at the level of the kidneys (e.g., central or nephrogenic
diabetes insipidus), hypernatremia is avoided if thirst is intact and access to free water is
maintained in adequate amounts to compensate for renal losses.
Hypernatremia is not always associated with pure water loss. It can be associated with
concomitant loss of sodium via hypotonic fluids (e.g., diarrheal fluid) or the addition of
hypertonic fluids (e.g., excessive sodium from parenteral nutrition or sodium bicarbonate
Hypernatremia causes a loss of intracellular water into the ECF space and can be associated
with cellular shrinkage. In the CNS, this can be catastrophic, with ensuing cell death or
rupture of blood vessels. To protect against cell shrinkage, electrolytes enter into the ICF,
usually in the first few hours. When hypernatremia persists beyond 2 or 3 days, the cells
begin to generate intracellular osmolytes to maintain intracellular fluid (ICF) osmolarity
further and avoid water loss into the ECF.
Hypokalemia can result from transcellular shifts (from extracellular into intracellular spaces),
or when potassium losses are increased; these losses can be from renal or nonrenal causes.
Transcellular shifts can occur in pathologic conditions associated with a catecholamine surge,
such as chest pain syndromes, or mediated by acid-base disturbances. Loop or thiazide
diuretic use, aldosteronism, or other renal diseases (e.g., postobstructive diuresis, cortical
necrosis) can cause excessive renal potassium losses. The renal and nonrenal causes of K+
loss can be determined by laboratory tests

More than 80% of hyperkalemic episodes are caused by impaired potassium excretion from
renal insufficiency. Usually, another event that prevents or overcomes the renal adaptation
precipitates the hyperkalemia. Supplemental potassium chloride administration is commonly
the second event and this added potassium can be from exogenous (e.g., diet, salt substitutes)
or endogenous sources (e.g., tumor lysis, gastrointestinal bleed, rhabdomyolysis). Impaired
K+ excretion or impaired potassium entry into cells accounts for all other causes of
hyperkalemia. Drugs such as potassium-sparing diuretics (e.g., spironolactone, triamterene),
or drugs that block aldosterone production or receptors (e.g., eplerenone, angiotensin-
converting enzyme [ACE] inhibitors, nonsteroidal anti-inflammatory drugs [NSAIDs],
heparin) impair the excretion of K+. Potassium entry into cells is impaired with insulin
deficiency, hypertonicity, or drugs (e.g., beta blockers, digoxin).
Phosphorus homeostasis is normally maintained through several mechanisms. GI absorption
must be matched by renal excretion, and cellular release is balanced by uptake in other
tissues. Hyperphosphatemia occurs when the phosphorus load (from GI absorption,
exogenous administration, or cellular release) exceeds renal excretion and tissue uptake, an
imbalance that can result from any of the following three pathogenic mechanisms:
 Excessive phosphate intake
 Decreased phosphate excretion
 Phosphate shift from intracellular to extracellular space
Regardless of the cause, hyperphosphatemia produces similar signs and symptoms. Because
phosphate is predominantly an intracellular anion and because a variety of factors can
regulate the actual serum phosphate concentration, an individual can ingest a very substantial
phosphate load without exhibiting frank hyperphosphatemia. Conversely, hyperphosphatemia
does not always reflect a true increase in total body phosphate stores.
Excessive phosphate intake
Excessive phosphate intake alone is an uncommon cause of hyperphosphatemia, particularly
in the presence of normal renal function. The mechanisms for renal excretion allow a person
with normal phosphate homeostatic mechanisms to ingest virtually unlimited quantities of
phosphate. In healthy persons, higher phosphate ingestion results in higher baseline serum
phosphate and higher peaks. Serum phosphate exhibits a diurnal rhythm, with the lowest
concentrations being at 8 AM and the highest at 4 PM and 4 AM. Antacids decrease
absorption because calcium, aluminum, and magnesium bind phosphorus into insoluble
complexes. Aluminum is the most efficient binder found in antacids.
Most often, hyperphosphatemia is caused by a relatively high phosphate intake in the setting
of impaired mechanisms for renal phosphate excretion (eg, renal failure, milk-alkali
Vitamin D intoxication can produce hyperphosphatemia as a result of excessive
gastrointestinal absorption and increased renal reabsorption.
Reports indicate that the excessive use of phosphate-containing laxatives or enemas can also
produce hyperphosphatemia. In addition, hyperphosphatemia can result from the short-term
parenteral administration of large quantities of phosphate, but again, this most often happens
in the setting of impaired renal function.
Decreased phosphate excretion
Renal failure
Decreased excretion of phosphate, especially when coupled with excessive intake, is by far
the most common mechanism for the development of hyperphosphatemia. The most common
cause of decreased renal phosphate excretion is kidney failure, acute or chronic, of any cause
(although marked hyperphosphatemia is unusual in chronic renal insufficiency unless the
glomerular filtration rate (GFR) is less than 25 mL/min).
Once renal insufficiency progresses to the loss of 40-50% of renal function, the decrease in
the amount of functioning renal tissue does not allow excretion of the full amount of ingested
phosphate required to maintain homeostasis, and hyperphosphatemia develops.
Hyperphosphatemia may persist when patients with end-stage renal disease are placed on
dialysis. Even in patients who are adherent to diet and prescribed phosphate binders, one or
more of the following may be involved [12] :
 Removal of phosphate by dialysis may vary by >400 mg per treatment
 Enteral absorption of phosphate may differ by ≥250 mg/d among patients, even with
correction for diet and vitamin D intake
 Efficacy of phosphate binder therapy may vary 2-fold among patients
Hypoparathyroidism causes hyperphosphatemia through a failure of the kidneys to inhibit
renal proximal tubule phosphate reabsorption. Syndromes of tubular resistance to PTH
manifest hyperphosphatemia because of the same mechanism. These syndromes include the
various types of pseudohypoparathyroidism (1a, 1b, 1c, and 2) and severe hypomagnesemia,
which impairs PTH secretion and causes peripheral PTH resistance.
Syndromes of tumoral calcinosis
The syndromes of tumoral calcinosis also are characterized by decreased renal excretion of
phosphate, resulting in hyperphosphatemia. [13, 14, 15, 16, 17] These syndromes are produced by
inactivating mutations of the following:
 FGF23, a phosphaturic hormone
 GALNT3, an enzyme that controls FGF23 glycosylation and function
 Klotho, an essential cofactor for the phosphaturic effect of FGF23 in the renal tubule
Vitamin D intoxication
Vitamin D intoxication, in addition to increasing gastrointestinal phosphate absorption,
increases renal phosphate reabsorption, thus enhancing the hyperphosphatemic effect.
Phosphate shift from intracellular to extracellular space
This pathogenic mechanism alone is an uncommon cause of hyperphosphatemia, but it can
exacerbate hyperphosphatemia produced by impaired renal excretion. Clinical situations in
which a shift to extracellular space is the major cause of hyperphosphatemia include
rhabdomyolysis and tumor lysis. Rarely, extracellular shifts of phosphate occur with insulin
deficiency or acute acidosis.
Sequelae of hyperphosphatemia
By precipitating calcium, decreasing vitamin D production, and interfering with PTH-
mediated bone resorption, hyperphosphatemia can cause hypocalcemia; in severe cases,
hypocalcemia can be life-threatening.
Prolonged hyperphosphatemia promotes soft-tissue calcification, in which an abnormal
deposition of calcium phosphate occurs in previously healthy connective tissues, such as
cardiac valves, and in solid organs, such as muscles.
Excess free serum phosphate is taken up into vascular smooth muscle via a type 3 sodium-
phosphate cotransporter. The increased cellular phosphate activates a gene, CBFA1, that
triggers a transformation in the vascular cell, causing smooth muscle cells to engage in
osteogenesis. Vascular walls become calcified and arteriosclerotic, leading to increased
systolic blood pressure, widened pulse pressure, and subsequent left ventricular hypertrophy.
However, although hyperphosphatemia is ultimately responsible for the increase in vascular
calcifications, studies have suggested that the process may additionally be influenced by 1,25
vitamin D and an elevated calcium-phosphate product .
Related disorders
Hyperphosphatemia is an independent risk factor contributing to the increased incidence of
aortic and mitral stenosis and other cardiovascular diseases among patients who are
dependent on dialysis. A peripheral form known as calcific uremic arteriolopathy
(calciphylaxis) can induce necrotic ulceration and gangrene in affected extremities.
Hyperphosphatemia-induced resistance to PTH contributes to secondary hyperparathyroidism
and renal osteodystrophy. [18]
Cardiovascular effects
Serum phosphate level is associated with cardiovascular risk even in individuals without
kidney disease in whom the serum phosphate is within the normal range. [19]
Studies have shown that acute phosphate loads obtained through dietary ingestion cause
endothelial cell dysfunction, manifested as a decrease in flow-mediated dilation, in healthy
men. This finding raises the possibility that the prolonged and chronic hyperphosphatemia
seen in patients with chronic kidney disease could play a direct role in the enhanced
cardiovascular morbidity and mortality seen in these patients. [20] A study in 70 patients who
were receiving regular peritoneal dialysis found that hyperphosphatemia (as well as high-
sensitivity C-reactive protein) was an independent risk factor for the initiation of coronary
artery calcification. [21]
Osseocartilaginous effects
Phosphate is a major mineral component of bone; not surprisingly, therefore, chronic
phosphate excess results in bone pathology, which occurs through several different
Some experimental evidence indicates that high phosphate levels are toxic to some cells.
Specifically, a high ambient phosphate level causes apoptosis of chondrocytes and osteoblasts
in cell culture. During growth, apoptosis stimulated by high phosphate levels is critical for
normal bone development. [22] However, the effect of chronic hyperphosphatemia on bone and
cartilage metabolism after closure of the growth plates is unknown.
Hyperphosphatemia complexes serum calcium, leading to lower-than-normal levels of
ionized calcium. The decrease in ionized calcium triggers the release of PTH, resulting in a
state of secondary hyperparathyroidism; high phosphate levels alone also stimulate PTH
release. The elevated PTH levels lead to a high bone turnover state, resulting in the release of
calcium, at the expense of bone, to normalize the serum calcium level.
High phosphate levels also inhibit 1-alpha hydroxylase, a renal enzyme that produces active
vitamin D by adding a hydroxyl group to circulating 25-hydroxycholecalciferol. This
inhibition is most likely a result of the hyperphosphatemia-stimulated increase in FGF23
The decrease in active vitamin D results in impaired gastrointestinal absorption of calcium,
decreased renal reabsorption of calcium and phosphate, and impaired bone mineralization.
Over months to years, bone density decreases. Additionally, the PTH and vitamin D
derangements result in abnormal bone architecture. Clinically, the skeletal manifestations of
chronic hyperphosphatemia include bone pain and fractures.
Soft-tissue calcification
Hyperphosphatemia, especially if present for an extended period, can lead to soft-tissue
calcification, that is, the deposition of calcium phosphate in nonosseous sites. For example,
patients with renal failure who have chronically uncontrolled hyperphosphatemia develop
progressively extensive soft tissue calcifications.
Major sites of calcium deposition include the eyes, joints, and vasculature. Joint deposits can
become large and painful, limiting movement and necessitating surgical removal, while eye
deposits produce the syndrome of band-shaped keratopathy and conjunctivitis.
Deposition of calcium/phosphate into skin causes a papular rash and may contribute to
uremic pruritus and ischemic ulcers. Calcium deposition in tendons and ligaments results in a
high frequency of spontaneous rupture.
The long-term complications of chronic hyperphosphatemia can affect any organ system and
are potentially devastating.
Vascular calcifications
Undoubtedly, the most significant long-term complication of chronic, uncontrolled
hyperphosphatemia is the development of vascular calcifications. These can assume the
following 3 basic forms:
 Capillary and small arteriole calcifications
 Medial arterial calcifications
 Cardiac calcifications
Vascular calcifications produce syndromes of accelerated coronary atherosclerosis, medial
arterial calcification, and calciphylaxis (which has been recognized and reported for many
years in patients with renal failure).
Capillary and small arteriole deposition of calcium is generally the pathology detected in
classic calciphylaxis. The blood supply distal to the calcified vessels is impaired, leading to
the development of necrotic skin lesions and hemorrhagic subcutaneous lesions.
Although many case reports have been published describing the syndrome of calciphylaxis,
research has been lacking; only a few series have included more than several patients. The
syndrome’s pathogenesis is not known. Several investigators have suggested a role for
hyperparathyroidism, excessive vitamin D, vitamin K deficiency, and high calcium phosphate
production. However, many patients may not demonstrate any of these abnormalities. In
contrast, most patients have a history of uncontrolled phosphate levels, implicating
hyperphosphatemia as a particularly important pathogenic or inciting factor.
Medial arterial calcium deposition has been described in patients with renal failure. Some
investigators suggest that smooth muscle cells in the media dedifferentiate into cells with a
more osteoblastic phenotype, allowing mineralization of the blood vessel. Support for this
theory comes from studies demonstrating the expression of osteoblast-specific proteins, such
as alkaline phosphatase and osteopontin, in the medial cells of calcified blood vessels. Other
investigators suggest that loss of normal inhibitors of soft tissue calcification, such as matrix
GLA protein or osteoprotegerin, may play a role in the pathogenesis.
A study also demonstrated that phosphate uptake through Pit-1, a type III sodium-dependent
phosphate cotransporter, is essential for smooth muscle cell calcification in response to
elevated phosphate. Studies on coronary calcification have uniformly shown a higher degree
of calcification at a younger age in patients with renal failure than in those without renal
failure. This premature coronary calcification is thought to play a role in the accelerated
cardiovascular mortality observed in patients with renal failure.
Calcium deposited into the heart tissue itself can disrupt the cardiac conduction system,
producing significant arrhythmias. Calcium deposition into valves generally does not produce
valve dysfunction, but it can serve as a marker for generalized vascular calcification. Aortic
valve calcification detected using echocardiography is a poor prognostic factor in patients
with renal failure and portends a high chance of mortality.
The precise role of uremia in causing, facilitating, or exacerbating the incidence and effect of
vascular calcifications associated with hyperphosphatemia has not been clarified.
Sumber :

Any of the following three pathogenic mechanisms can cause hypophosphatemia:
 Inadequate intake
 Increased excretion
 Shift from extracellular to intracellular space
Inadequate intake
Inadequate phosphate intake alone is an uncommon cause of hypophosphatemia. The ease of
intestinal absorption of phosphate coupled with the ubiquitous presence of phosphate in
almost all ingested food substances ensures that daily phosphate requirements are more than
met by even a less-than-ideal diet.
Hypophosphatemia is most often caused by long-term, relatively low phosphate intake in the
setting of a sudden increase in intracellular phosphate requirements such as occurs with
refeeding. Intestinal malabsorption can contribute to inadequate phosphate intake, especially
if coupled with a poor diet. Although generally not essential for adequate phosphate
absorption, vitamin D deficiency can contribute to hypophosphatemia by failing to stimulate
phosphate absorption in cases of poor dietary ingestion. Case reports also document patients
developing hypophosphatemia due to excessive use of antacids, particularly calcium-,
magnesium-, or aluminum-containing antacids.
Increased excretion
Increased excretion of phosphate is a more common mechanism for the development of
hypophosphatemia. The most common cause of increased renal phosphate excretion is
hyperparathyroidism due to the ability of PTH to inhibit proximal renal tubule phosphate
transport. However, frank hypophosphatemia is not universal and is most often mild.
Increased excretion of phosphate can also be induced by forced saline diuresis due to the
inhibitory effect of saline diuresis on all proximal renal tubule transport processes. Again, the
degree of hypophosphatemia is generally minimal. Vitamin D deficiency not only impairs
intestinal absorption, but also decreases renal absorption of phosphate.
Several genetic and acquired syndromes of phosphate wasting and associated skeletal
abnormalities have been described. These include syndromes characterized by isolated
proximal tubule phosphate wasting, such as the congenital or acquired rickets syndromes
described previously, and Fanconi syndrome, in which phosphate wasting represents one
component of a generalized proximal tubule dysfunction. Congenital Fanconi syndromes
include Wilson disease and cystinosis, while acquired Fanconi syndrome can be seen with
several medications, paraproteinemias, connective tissue disorders, and heavy metals. [19, 20, 21]
Shift from extracellular to intracellular space
This pathogenetic mechanism alone is an uncommon cause of hypophosphatemia, but it can
exacerbate hypophosphatemia produced by other mechanisms. Clinical situations in which
this mechanism is the major cause of hypophosphatemia are the treatment of diabetic
ketoacidosis, refeeding, short-term increases in cellular demand (eg, hungry bones
syndrome), and acute respiratory alkalosis