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In SIADH, Uosm is inappropriately high for Posm and is relatively
fixed. Only solutions with higher osmolarity than urine can raise SNa
+
(see Table 2). Thus, 0.9% saline will worsen hyponatremia if Uosm is
greater than 308 mOsm/L and therefore has only a minor role in SIADH,
except perhaps for the correction of coexisting volume depletion. Loop
diuretics (e.g. furosemide) can be used in conjunction with 3% saline to
lower Uosm and thus facilitate free water excretion. Intravenous (conivaptan) or oral (tolvaptan) vasopressin receptor antagonists are
approved for and may have a role in the treatment of SIADH.
Disadvantages of vaptan use include the potential for overly rapid correction of hyponatremia, increased thirst, and high cost. Demeclocycline
and lithium can induce resistance to ADH and increase free water
excretion, but are rarely used to treat SIADH.
Hypernatremia
Hypernatremia is defined as SNa+>145 mEq/L. It develops due to loss of
hypotonic fluid (loss of water in excess of sodium) or, less commonly, due
to excessive gain of sodium.
444
Z. C. Alsauskas and M. J Ross
Table 2. Intravenous Solutions Used for Treatment of Sodium
Disorders
D5W — dextrose (5% in water) ½ NS — 0.45% Saline
Dextrose 5 g/100 mL NaCl 0.45 g/100 mL
Total osm 278 mOsm/L Na
+
77 mEq/L
(consider this as a source of free Cl
−
77 mEq/L
water, as dextrose is rapidly Total osm 154 mOsm/L
taken up by cells and
metabolized)
NS — 0.9% Saline 3% Saline
NaCl 0.9 g/100 mL NaCl 3.0 g/100 mL
Na
+
154 mEq/L Na+513 mEq/L
Cl
−
54 mEq/L Cl−513 mEq/L
Total osm 308 mOsm/L Total osm 1026 mOsm/L
Hypernatremia rarely develops in a mobile alert person with adequate
access to water and an intact thirst mechanism. In contrast, patients with
altered mental status, immobility, or no access to water are prone to hypernatremia (infants, critically ill or nursing home patients). Impairment of
thirst (hypodipsia) is uncommon.
Extrarenal hypotonic fluid losses occur with osmotic diarrhea (secretory
diarrhea causes isotonic fluid losses), increased sweating, and increased
respiratory water loss (fever, mechanical ventilation).
Central diabetes insipidus (CDI) occurs due to a defect of ADH
production or secretion, whereas nephrogenic diabetes insipidus (NDI)
is characterized by renal resistance to the action of ADH. (See Table 3
for a list of etiologies of CDI and NDI.) In diabetes insipidus,
urine cannot be appropriately concentrated in the setting of elevated
effective Posm, resulting in free water loss. Depending on the severity
of the concentrating defect, diabetes insipidus can be complete (Uosm
<300 mOsm/L) or partial (Uosm = 300–800 mOsm/L). Renal hypotonic fluid loss causing hypernatremia can also occur with osmotic
diuresis due to hyperglycemia or mannitol, or, less commonly, with
loop diuretics.
Sodium overload is an uncommon cause of hypernatremia and may
occur due to hypertonic sodium bicarbonate administration during cardiopulmonary resuscitation, inadvertent hypertonic saline infusion, or
massive oral salt ingestion. Mineralocorticoid excess can cause mild
hypernatremia (usually <150 mEq/L) by resetting the osmostat to cause
ADH secretion at higher effective Posm.
445
Hyponatremia and Hypernatremia
Table 3. Etiologies of Central and Nephrogenic Diabetes Insipidus
Central Diabetes Insipidus Nephrogenic Diabetes Insipidus
• Idiopathic • Primary or metastatic • Hereditary • Sickle cell
• Neurosurgery brain tumors • Hypercalcemia nephropathy
• Head trauma • Infiltrative disorders • Hypokalemia • Sjögren’s
• Cerebral anoxia (sarcoidosis, • Lithium toxicity syndrome
or ischemia histiocytosis X) • Ifosfamide • Amyloidosis
Workup (also see Fig. 3)
History
• Symptoms of hypernatremia: weakness, lethargy, seizures, or coma.
• Clues to etiology in history: hypovolemia or volume overload, renal
or extrarenal fluid losses, potential etiologies for CDI or NDI.
• Polyuria (without hyponatremia) in patients with diabetes insipidus
and adequate water intake.
Physical exam
• Assessment of volume status (see section on hyponatremia).
446
Z. C. Alsauskas and M. J Ross
Fig. 3. Approach to hypernatremia.
Hypernatremia
Check volume status
Hypovolemic
hypernatremia
Loss of water in excess
of sodium and
insufficient water intake
Extrarenal losses
(UNa+ <20,
Uosm >800,
Low Uvol
Diarrhea
Vomiting
Sweating
Osmotic diuresis
(>1000 mosm/24 hr,
UNa+>40, Uosm <800,
polyuria)
Hyperglycemia
Mannitol
Loop diuretics
Euvolemic
hypernatremia
(may have signs of
volume depletion)
Predominant loss of
water and insufficient
water intake
Water diuresis
(<800 mOsm/24 hr)
Uosm <300 mOsm/L
Complete central
diabetes insipidus
Complete nephrogenic
diabetes insipidus
Uosm = 300–800 mosm/L
Incomplete central
diabetes insipidus
Incomplete nephrogenic
diabetes insipidus
Hypervolemic
hypernatremia
Gain of sodium
Salt ingestion
Hypertonic saline
Hypertonic NaHCO
Mineralocorticoid
excess
-
3
Labs
• Uosm, UNa+.
• Serum sodium, potassium, bicarbonate, urea nitrogen, creatinine, and
glucose.
• The water restriction test may need to be performed in a consultation
with a nephrologist to differentiate between psychogenic polydipsia,
CDI and NDI.
Treatment
Treatment of hypernatremia should be aimed at correcting the underlying
condition, restoring access to water, and normalizing SNa
+
. The decrease
in SNa
+
must be limited to <10 mEq/L/24 hr in order to avoid cerebral
edema, especially if the hypernatremia is chronic (>2 days). More rapid
correction may be appropriate if the hypernatremia causes severe
symptoms.
In renal and extrarenal hypotonic fluid losses, treatment should be
aimed at repleting the volume deficit and correcting the free water deficit.
The volume deficit must be corrected quickly with 0.9% saline infusion,
especially if it causes tissue hypoperfusion and organ dysfunction (e.g.
hypotension, renal failure). Free water deficit can be slowly corrected by
oral or intravenous free water administration (see Table 3 for available
intravenous solutions). Formulas and sample calculations for estimating
initial infusion rates are provided in Fig. 2. Note that these calculations do
not always accurately predict the change in SNa
+
and do not take into
account ongoing renal and extrarenal losses of water and solutes,
and therefore close monitoring of SNa
+
is essential in order to prevent
overcorrection.
Central diabetes insipidus is treated with oral or intranasal desmopressin (dDAVP). The lowest effective dose that controls polyuria is used
to minimize the risk of SIADH and hyponatremia. Nephrogenic diabetes
insipidus can be treated by inducing mild volume depletion with dietary
sodium restriction and thiazide diuretics, hence increasing proximal
447
Hyponatremia and Hypernatremia
tubular fluid absorption and minimizing distal delivery and water loss.
A low protein diet decreases daily urinary osmole load (urea) and may
improve polyuria. Amiloride can be used with thiazides to facilitate diuresis and prevent potassium depletion; it is uniquely useful in lithiuminduced NDI by blocking its entry into tubular cells.
References
1. Adrogué HJ, Madias NE. (2000) Hyponatremia. New Engl J Med
342(21): 1581–1589.
2. Adrogué HJ, Madias NE. (2000) Hypernatremia. New Engl J Med
342(20): 1493–1499.
3. Nguyen MK, Ornekian V, Butch AW, Kurtz I. (2007) A new method
for determining plasma water content: Application in pseudohypona-
tremia. Am J Physiol Renal Physiol 292(5): F1652–F1656.
4. Ellison DH, Berl T. (2007) Clinical practice. The syndrome of inap-
propriate antidiuresis. New Engl J Med 356(20): 2064–2072.
5. Brown WD. (2000) Osmotic demyelination disorders: Central pontine
and extrapontinemyelinolysis. Curr Opin Neurol 13(6): 691–697.
6. Decaux G, Soupart A, Vassart G. (2008) Non-peptide arginine-
vasopressin antagonists: The vaptans. Lancet 371: 1624–1632.
7. Schrier RW, Gross P, Gheorghiade M, et al. (2006) Tolvaptan, a selec-
tive oral vasopressin V2-receptor antagonist, for hyponatremia. New
Engl J Med 355(20): 2099–2112.
8. Gheorghiade M, Konstam MA, Burnett JC Jr, et al. (2007) Short-term
clinical effects of tolvaptan, an oral vasopressin antagonist, in patients
hospitalized for heart failure: The EVEREST Clinical Status Trials.
JAMA 297(12): 1332–1343.
9. Konstam MA, Gheorghiade M, Burnett JC Jr, et al. (2007) Effects of
oral tolvaptan in patients hospitalized for worsening heart failure: The
EVEREST Outcome Trial. JAMA 297(12): 1319–1331.
448
Z. C. Alsauskas and M. J Ross
Disorders of Potassium Homeostasis
Raj K. Medapalli†and Michael J. Ross*
Key Pearls
• When hyperkalemia develops in a nonoliguric patient with mild-to-
moderate renal failure, renal failure is seldom the cause of hyper-
kalemia, and other concomitant causes should be sought.
• If ECG changes of hyperkalemia are present, emergent treatment is
necessary and IV calcium should be given first to stabilize the cardiac
cell membranes, in addition to interventions to lower the levels of
plasma potassium.
• Hypomagnesemia is present in about 40% of patients with hypokalemia,
and its correction minimizes urinary potassium losses and is a crucial
component of the treatment for hypokalemia.
• Random urine potassium–creatinine ratio values greater than 25 mEq/g
suggest inappropriately high renal potassium excretion in the setting of
hypokalemia.
• Avoid administering intravenous potassium mixed in dextrose solu-
tions (dextrose can lead to redistribution of potassium into cells) or in
normal saline (the solution will become hypertonic). Use half-isotonic
saline or sterile water for injection (SWI).
Introduction
The average dietary intake of potassium is 40–120 mEq/day.1The body
handles this potassium load initially by transporting a portion of it
449
38
Chapter
*Mount Sinai School of Medicine, New York, NY, USA.
into cells, which curtails the acute rise in the plasma potassium concentration, and subsequently by eliminating most of the potassium in the
urine within 6–8 hr.
2
Plasma concentrations of potassium, insulin and epinephrine are the
major factors that promote entry of potassium into cells. An increase in
plasma potassium or stimulation of insulin receptors or β
2
adrenergic
receptors increases the activity of the sodium–potassium (Na–K)-ATPase
pump.
The rate of potassium excretion in the urine is determined primarily
by potassium secretion in the renal collecting tubule, as almost all of the
filtered potassium is reabsorbed in the proximal tubule. Potassium secretion is regulated chiefly by the concentration of plasma potassium, the
effect of aldosterone and the quantity of sodium and water delivered to the
distal nephron.
Hyperkalemia
Hyperkalemia is defined as a plasma potassium concentration greater than
5.3 mEq/L.
Etiology
Hyperkalemia can develop due to increased potassium intake, impaired
excretion of potassium, release of intracellular potassium or, often, due to
a combination of these processes. It is important to note that potassium
homeostasis is usually well-maintained even in patients with moderate
renal failure because of an adaptive increase in Na–K-ATPase activity
in the remaining functioning nephrons. Therefore, when hyperkalemia
develops in a nonoliguric patient with mild-to-moderate renal failure,
other concomitant causes of hyperkalemia should be sought. The causes
of transcellular shifting of potassium and impaired excretion are outlined
in Fig. 1.
450
R. K. Medapalli and M. J. Ross
451
Disorders of Potassium Homeostasis
T
Fig. 1. Eitiologies of hyperkalemia organized by pathomechanism.
Etiology of hyperkalemia
ranscellular shift
of pot
assium
Pseudohyperkalemia
Hemolysed blood specimen
Marked leucocytosis
Marked thrombocytosis
Heriditary sperocytosis
Familial pseusohyperkalemia
Metabolic Acidosis
Increased tissue catabolism
Rhabdomyolysis
Tumor lysis syndrome
Insulin deficiency
Diabetes mellitus
Fasting (e.g. pre-operatively)
in dialysis patients
Somatostatin use
Hyperosmolality
Hyperglycemia
Mannitol
Hypernatremia
Medications
Inhibition of beta-2 mediated K-uptake
- Non-selective beta blockers
Inhibition of Na-K-ATPase pump
- Digitalis
Cell membrane K-channel activators
- Calcineurin inhibitors
- Minoxidil
- Diazoxide
Patients with severe burns
immobility or neuromuscular disease
- Succinylcholine
Key: LMWH: low molecular weight heparin, ACEI: angiotensin converting enzyme inhibitors,
ARB: angiotensin receptor blockers, NSAIDS: non-steroidal anti-inflammatory drugs,
CT: collecting tubule, RTA: renal tubular acidosis.
, prolonged
Reduced excretion
of potassium
Advanced renal failure
Aldosterone deficiency
Primary
- Primary adrenal insufficiency
- Primary hypoaldosteronism
- Congenital adrenal hyperplasia
- Heparin and LMWH
Hyporenemic hypoaldosteronism
- Renal disease, most often
diabetic kidney disease
- Volume expansion, as in
acute glomerulonephritis
- ACEI, ARB, direct renin inhibitors
- NSAIDS
- C
closporine
y
- HIV infection
Aldosterone resistance
Aldosterone antagonists
- Sprinonolactone
- Eplerenone
CT sodium channel blockers
- Amiloride
- Triamterene
- Trimethoprim
- Pentamidine
Tubulointerstitial disease
Pseudohypoaldosteronism
Distal chloride shunt
Effective volume depletion
Heart failure
Cirrhosis
Salt wasting nephropathy
Hyperkalemic type-1 RTA
Sickle cell disease
Obstructive uropathy
Ureterojejunostomy
Clinical Manifestations
Signs and Symptoms
Symptoms of hyperkalemia are rare until the potassium concentration
exceeds 6.5 mEq/L, unless the rise in the potassium concentration occurs
very rapidly. When symptomatic, hyperkalemia manifests with muscle
weakness and/or palpitations. Muscle weakness often develops in an
ascending pattern and can progress to flaccid paralysis. Hyperkalemia can
induce arrhythmias that can lead to cardiac arrest (see “ECG manifestations,” below).
ECG Manifestations
The earliest ECG sign of hyperkalemia is tall, peaked T waves with a
shortened QT interval, followed by progressive lengthening of the
PR interval, widening of the QRS complex and eventual disappearance of
the P wave. The widened QRS complex ultimately merges with the T
wave to produce a sine-wave pattern, followed by ventricular fibrillation
and, eventually, asystole. However, not all patients follow this classical
progression and the initial ECG manifestation of hyperkalemia can be
severe arrhythmia or cardiac arrest.
Workup
After ruling out fictitious causes of hyperkalemia (hemolysis during
venipuncture, severe thrombocytosis, etc.), patients should be worked up
to identify the underlying cause. The initial workup should include an
assessment of the chronicity of hyperkalemia, an electrocardiogram
and measurement of renal function. Any ongoing administration of
potassium-containing medications (e.g. IV fluids and TPN solutions with
potassium) should be discontinued. Conditions resulting in disturbances
in the transcellular movement of potassium (Fig. 1) should be ruled out.
If renal function is not severely impaired, the following additional tests
should also be performed:
452
R. K. Medapalli and M. J. Ross
Transtubular potassium concentration gradient
The transtubular potassium concentration gradient (TTKG) estimates
aldosterone activity by estimating the tubular fluid potassium concentration at the end of the cortical collecting tubule, where the majority of the
potassium secretion occurs. It is derived using the following formula:
TTKG = [urine potassium ÷ (urine osmolality/serum osmolality)] ÷
serum potassium
The TTKG is most accurate when the urine osmolality exceeds that of the
plasma and the urine sodium concentration is above 25 mEq/L.
The TTKG in normal patients is 8–9 on a regular diet and above 11
after a potassium load. Avalue below 7 in a hyperkalemic patient is highly
suggestive of hypoaldosteronism.
3
Plasma Aldosterone Concentration and Plasma Renin Activity
Plasma aldosterone concentration (PAC) and Plasma renin activity (PRA)
can be used in conjunction with the TTKG to narrow the differential diagnosis in hyperkalemic patients with normal renal function (see Fig. 2).
Treatment
Serum potassium concentration and ECG manifestations of hyperkalemia,
if present, are the primary determinants of the choice of initial treatment
(see Fig. 3). See Table 1 for information on dosing and pharmacodynamics of medications commonly used to treat hyperkalemia.
Emergent hemodialysis should be initiated in those patients who do not
respond to medical therapy and/or if there is ongoing release of intracellular potassium, as in cases of rhabdomyolysis and tumor lysis syndrome.
In addition to instituting therapy to lower the potassium levels, the
underlying cause of hyperkalemia should be sought and treated if possible. Volume status should be optimized and patients may require longterm dietary potassium restriction, treatment with loop or thiazide
453
Disorders of Potassium Homeostasis