A heavy urinary protein loss results in various extrarenal complications.

16,17

Hypoalbuminemia reduces plasma oncotic pressure and contributes to the increased

hepatic synthesis of both albumin and lipoproteins. This, coupled with the decreased

catabolism of lipoproteins, resulted in L.J.’s hyperlipidemia.

16,21 Urinary loss of

inhibitors of coagulation predispose these patients to thromboembolism.

16

Specific therapy of nephrotic syndrome ranges from simple removal of the

offending medication and treatment of the underlying comorbidities to the use of

immunosuppressive agents in specific glomerular diseases.

L.J.’s anasarca results from changes in both capillary hemodynamics and renal

sodium and water retention.

22 The hypoalbuminemia (2 g/dL) and proteinuria (>300

mg/dL) produce an imbalance in the Starling forces across the capillary wall, namely

the hydrostatic and oncotic pressures in the capillary and interstitial compartments.

The reduced capillary oncotic pressure favors movement of fluid from the vascular

space into the interstitium.

23 This leads to contraction of the effective arterial blood

volume, which in turn activates humoral, neural, and hemodynamic mechanisms that

signal the kidney to retain sodium and water.

24,25 This underfill hypothesis has been

challenged by data, suggesting that hypoalbuminemia plays a minor role in nephrotic

edema

26,27 and the observation that patients with nephrotic syndrome can have

increased, normal, or decreased plasma volumes.

23

A defect in the intrarenal sodium handling mechanism that causes inappropriate

sodium retention also contributes to nephrotic edema.

23,26 According to this overflow

hypothesis, proteinuric renal disease leads to increased sodium reabsorption in the

distal nephron. The mechanism is not well defined but may be related to cellular

resistance to atrial natriuretic peptide.

23 Thus, a sodium excess state occurs and

edema results. It is likely that the interaction between the underfill and overflow

mechanisms results in the production of nephrotic edema.

28 Patients with severe

hypoalbuminemia (i.e., serum albumin level < 1.5 g/dL), who have a severe

reduction in plasma oncotic pressure, are most likely to exhibit evidence of the

underfill phenomenon.

22

p. 573

p. 574

CASE 27-3, QUESTION 2: How should L.J.’s sodium excess state be managed?

The etiology of L.J.’s nephrotic syndrome should be identified for specific

treatment. Although L.J.’s serum sodium concentration of 132 mEq/L is low, it

reflects dilution secondary to fluid excess. Salt restriction is therefore important to

control L.J.’s generalized edema.

23 For most nephrotic patients, modest dietary

sodium restriction to approximately 50 mEq/day may be sufficient to maintain neutral

sodium balance.

22,23 For nephrotic patients who are very sodium avid (urine sodium

concentration < 10 mEq/L), sufficient restriction is difficult to achieve. Thus,

slowing the rate of edema formation rather than hastening its resolution should be the

goal of therapy for these patients.

23 Bed rest reduces orthostatic stimulation of the

renin–angiotensin–aldosterone and sympathetic systems, thereby favoring the

movement of interstitial fluid into the vascular space.

23 The central blood volume is

thus increased and natriuresis and diuresis are facilitated. Prolonged bed rest might,

however, predispose these hypercoagulable patients to thromboembolism.

16

Similarly, use of support stockings may reduce the stimulation for sodium retention

by redistributing blood volume to the central circulation.

23,29

DIURETICS

Usually, loop diuretics are the mainstay of therapy in the management of nephrotic

edema.

2,23

In most of these patients, the edema can be removed safely with rapid

diuresis without compromising the systemic circulation, probably because of the

rapid refilling of the plasma volume by interstitial fluid.

23 Nevertheless, as the edema

resolves, the rate of fluid removal and weight loss should be decreased to avoid

compromising the effective circulating volume. The patient should be monitored for

the development of orthostatic hypotension.

Infusions of albumin can expand the plasma volume; however, it is expensive, the

relief is temporary, and it should therefore be used only for resistant edema.

30

In

patients who are resistant to the aforementioned measures, extracorporeal fluid

removal, namely ultrafiltration, may be necessary.

23,31

L.J. was initially treated with IV furosemide 60 mg twice daily and placed on a

low-sodium (50 mEq), low-fat, high-complex carbohydrate diet that consisted of 0.8

g/kg protein of high biologic value with additional protein to match gram-per-gram of

urinary protein loss. Fluid was restricted to 1,000 mL/day.

32 He had 5 L of diuresis

in 2 days, with resolution of respiratory symptoms and a reduction in the anasarca.

Parenteral furosemide was discontinued on the fifth day of hospitalization and oral

furosemide 120 mg twice daily was started. After a total weight loss of 12 kg, he was

then discharged with instructions to maintain the diet and oral furosemide.

DISORDERS IN OSMOREGULATION

Hyponatremia

Serum sodium concentration reflects the ratio of total body sodium to total body

water and is not an accurate indicator of total body sodium. Both hyponatremia and

hypernatremia can occur in the presence of a low, normal, or high total body

sodium.

33,34

Because the kidney can excrete greater than 12 to 16 L of free water daily,

hyponatremia does not occur unless the water intake overwhelms the kidney’s ability

to excrete free water (e.g., psychogenic polydipsia),

35,36 or free-water excretion is

impaired.

2,37

Free-water formation requires a normal glomerular filtration rate (GFR), the

reabsorption of sodium chloride without water in the thick ascending limb of Henle’s

loop and the distal convoluting tubule, and the excretion of a dilute urine in the

absence of ADH37

(Fig. 27-1). Therefore, hyponatremia can occur when the kidney’s

diluting ability is exceeded or impaired owing to volume depletion and nonosmotic

stimulation of ADH release or inappropriate stimulation of ADH production.

2,37

Although plasma sodium is the primary determinant of plasma tonicity,

hyponatremia does not always represent hypotonicity.

2,37

In patients with severe

hyperlipidemia or hyperproteinemia (e.g., multiple myeloma), pseudohyponatremia

can occur because the increased amounts of lipids and proteins displace plasma

water, in which sodium ions dissolve, resulting in a lower concentration of sodium

per unit volume of plasma.

34,37,38 Normally, water accounts for 93% of the plasma

volume, and lipids and proteins make up the rest.

37 The increase in plasma lipid and

protein contents expands plasma volume, displaces water, and increases the

percentage of solids in plasma.

34,37 Because sodium is distributed only in the aqueous

phase, the sodium content per liter of the newly recomposed plasma is thus decreased

and the plasma sodium concentration is reduced.

34,37,38 The sodium concentration in

plasma water remains the same, however. Because osmolality depends on the solute

concentration in plasma water, serum osmolality remains unchanged.

34

Indeed, the

measured osmolality is normal. Another example of isotonic hyponatremia can be

found when a large volume of isotonic mannitol irrigant is used during prostate

surgery.

34,37 Absorption of the irrigation solution can result in severe hyponatremia

but normal osmolality. In contrast, use of large amounts of isotonic sorbitol and

isotonic, or slightly hypotonic, glycine solutions during urologic surgery can cause

the hypotonicity as a late complication.

34,37 Similar to mannitol, sorbitol and isotonic

glycine initially distribute only in the extracellular space, resulting in hyponatremia

without a change in osmolality.

37 Unlike mannitol, both sorbitol and glycine are later

metabolized, leaving water behind to result in hypotonicity. The severe hypotonic

hyponatremia, in conjunction with the neurotoxic effects of glycine and its

metabolites, puts the patient at significant risk for severe neurologic symptoms

(Table 27-1).

37,39

CASE 27-4

QUESTION 1: T.T., a 63-year-old man with end-stage renal disease caused by diabetic nephropathy, is

receiving chronic ambulatory peritoneal dialysis. Because of dietary and fluid noncompliance, T.T. complained

of shortness of breath (SOB) and his dialysis prescription was adjusted to include six cycles of 2.5% peritoneal

dialysis solutions. Today, his laboratory values are as follows:

Na, 128 mEq/L

K, 4 mEq/L

Cl, 98 mEq/L

Total CO2

, 24 mM

BUN, 50 mg/dL

Creatinine, 6 mg/dL

Glucose, 600 mg/dL

Evaluate T.T.’s plasma osmolality. What is the etiology of T.T.’s hyponatremia?

p. 574

p. 575

Table 27-1

Clinical Presentation and Treatment of Hyponatremia

Na+ and H2O

Status Clinical Presentation/Cause Treatment

Edematous, Fluid Overload (Hypervolemic, Hypotonic)

↑ Total body Na+–

↑↑

Total body H2O

Cirrhosis/HF/nephrotic syndrome: A ↓ in

renal blood flow activates renin–angiotensin

system. ↑ Aldosterone leads to ↑ Na+, and

↑ ADH leads to free H2O retention. Urine

Na+ is low (0–20 mEq/L) and urine

osmolality ↓. Diuretics can induce

paradoxical effects on urine Na+ and

osmolality. This form can also occur in

patients with renal failure who drink

excessive amounts of water. Patients have

symptoms of fluid overload (ascites,

distended neck veins, edema).

Fluid and Na+ restriction. Correct

underlying disorder (e.g., paracentesis for

ascites). Diurese cautiously

a

; avoid ↓ ECF

and accompanying ↓ tissue perfusion. ↑

BUN may indicate overly rapid diuresis.

Conivaptan: Loading dose of 20 mg IV for

30 minutes, followed by 20 mg IV as

continuous infusion for 24 hours for an

additional 1 to 3 days; may titrate up to

maximal dose of 40 mg/day; maximal

duration is 4 days after the loading dose.

Dedicated IV line recommended and site of

peripheral IV lines should be changed every

24 hours. Caution if used together with fluid

restriction.

Tolvaptan: Start 15 mg PO once daily.

Dose may be increased at intervals of at

least 24 hours to 30 mg PO once daily and

then to a maximum of 60 mg PO once daily

as needed. Caution if used together with

fluid restriction. Initiate therapy in a hospital

setting.

Nonedematous Hypovolemic (Hypotonic with ECF Depletion)

↓↓ Total body Na+

↓ Total body H2O

Occurs in GI fluid loss (e.g., diarrhea) with

hypotonic electrolyte-poor fluid

replacement, overdiuresis, “third spacing,”

Addison disease, renal tubular acidosis,

osmotic diuresis. Replacement of fluid

losses with solute-free fluid predisposes

these patients to hyponatremia. Kidneys

Discontinue diuretics. Replace fluid and

electrolyte (especially K+) losses. 0.9%

saline preferred unless Na+ deficit

a

severe,

then use 3%–5% saline.

concentrate urine to conserve fluid (urine

Na+ <10 mEq/L). Symptoms:

nonedematous; ECF depletion (collapsed

neck veins, dehydration, orthostasis).

Neurologic symptoms: (see Hyponatremia:

Neurologic Manifestations in text).

Nonedematous, Normovolemic (Normovolemic, Hypotonic)

↓ Total body Na+

↑ Total body H2O

SIADH

b

: Hyponatremia, hypo-osmolality,

renal Na+ wasting (>40 mEq/L), absence

of fluid depletion, Uosm > Posm, normal

renal and adrenal function. Free H2O

retained while Na+ lost. Causes: (a) ADH

production (infectious disease, vascular

disease, cerebral neoplasm, cancer of lung,

pancreas, duodenum); (b) exogenous ADH

administration; (c) drugs; (d) psychogenic

polydipsia.

See earlier for dosing of VRA (conivaptan

and tolvaptan)

Chronic treatment: Restrict fluids to less

than urine loss. Demeclocycline (300–600

mg BID) induces reversible diabetes

insipidus. Emergency treatment for

unresponsive patients includes furosemide

diuresis to achieve negative H2O balance

with careful replacement of Na+ and K+

using hypertonic saline solutions.

c

aRemove estimated excess free water with IV furosemide (1 mg/kg). Repeat as necessary. Because furosemide

generates a urine that resembles 0.5% NaCl, urine losses of sodium and potassium must be carefully measured and

replaced hourly with hypertonic salt solutions. Correction rate: 1 to 2 mEq Na/hour in symptomatic patients; 0.5

mEq/hour in asymptomatic patients.

bEstimate sodium deficit: (mEq) = TBW (sodium desired − sodium observed). Rate of sodium and fluid repletion

used depends on severity. Mild: replace with NS. First one-third for 6 to 12 hours at a rate of <0.5 mEq/L/hour,

remaining two-thirds for 24 to 48 hours. Severe (e.g., seizures): Use 3% to 5% saline, rate gauged by patient’s

ability to tolerate sodium and volume load. Monitor central nervous system function, skin turgor, blood pressure,

urine sodium, signs of sodium or water overload, especially in patients with cardiovascular, renal, and pulmonary

disease.

cTotal body water (TBW) = 0.6 L/kg × weight in kg (for men) and 0.5 L/kg × weight in kg (for women).

TBW excess = TBW − [TBW (observed serum NA)/(desired serum NA)].

ADH, antidiuretic hormone; BID, twice daily; BUN, blood urea nitrogen; HF, heart failure; ECF, extracellular fluid;

GI, gastrointestinal; IV, intravenous; NS, normal saline (0.9% Na); PO, orally; SIADH, syndrome of inappropriate

ADH; TBW, total body weight.

T.T.’s effective plasma osmolality is calculated to be 289 mOsm/L, of which 33

mOsm/L is contributed by the hyperglycemia. The slow utilization of glucose,

because of the lack of insulin, causes water to move from the intracellular

compartment into the plasma space because of the increased tonicity, thereby

lowering the plasma sodium concentration.

34,37 Despite the lowered plasma sodium

concentration, the plasma osmolality is normal because of hyperglycemia. Hence, no

symptoms attributable to hypo-osmolality are observed. Indeed, when serum glucose

is normalized with insulin and hydration, the serum sodium level will increase to

approximately 136 mEq/L. For each 100-mg/dL increment in serum glucose, serum

sodium decreases by 1.3 to 1.6 mEq/L.

34,37 Use of hypertonic mannitol or glycine

solutions in patients with cerebral edema also results in a hyperosmolar

hyponatremia.

34

p. 575

p. 576

Hypotonic Hyponatremia with Decreased Extracellular

Fluid

CASE 27-5

QUESTION 1: Q.B., a 30-year-old male athlete who has had multiple bouts of diarrhea for the last several

days, has been drinking a sports drink to keep himself from getting dehydrated. His vital signs include supine

BP, 145/80 mm Hg, and pulse, 70 beats/minute; standing BP, 128/68 mm Hg, and pulse, 90 beats/minute.

Respiratory rate (RR) is 12 breaths/minute, and he is afebrile. His skin turgor is mildly decreased and laboratory

data are the following:

Na, 128 mEq/L

K, 3.0 mEq/L

Cl, 100 mEq/L

Bicarbonate, 17 mEq/L

BUN, 27 mg/dL

Creatinine, 1.2 mg/dL

Urinary sodium and chloride were both less than 10 mEq/L. Assess Q.B.’s electrolyte and fluid status. What

is the etiology of Q.B.’s hyponatremia?

Q.B. has true hypotonic hyponatremia with ECF depletion, suggesting that his total

body sodium deficit is greater than that of total body water.

34 His poor skin turgor,

orthostasis, prerenal azotemia, and low urinary sodium are consistent with volume

depletion. The urinary sodium concentration helps distinguish between renal and

nonrenal losses that result in the sodium and water deficits.

15,34,40 When the plasma

volume is depleted, the urinary sodium concentration is less than 10 mEq/L,

suggesting appropriate renal sodium conservation.

15 This is usually seen in patients

such as Q.B. with GI fluid loss as in vomiting, diarrhea, or profuse sweating.

34,37,40

Other causes of hypotonic hyponatremia are less likely in Q.B. They include

surreptitious cathartic abuse and “third spacing,” or accumulation of ECF in the

abdominal cavity during acute pancreatitis, ileus, or pseudomembranous colitis.

37,40

If

the urinary sodium is less than 20 mEq/L in the face of volume depletion, renal salt

wastage should be considered.

15,37,40 The potential causes of this latter problem

include diuretic use,

41–44 adrenal insufficiency,

44 and salt-wasting nephropathy

35

(e.g.,

chronic interstitial nephritis, medullary cystic disease, polycystic kidney disease,

obstructive uropathy, and cisplatin toxicity

44,45

). In patients with renal insufficiency,

neither the urinary sodium nor chloride concentration is a reliable index of volume

status.

15

Volume depletion leads to increased reabsorption of sodium and water in the

proximal tubule and, thus, decreased sodium delivery to the diluting segments for

free-water formation.

34,37,40 Decreased effective arterial volume is also a potent

nonosmotic stimulus for ADH release.

9,10 These factors combine to dampen the

ability of the kidney to form dilute urine and result in high urine osmolality despite a

low serum sodium concentration.

34,37,40 Although the fluid lost in diarrhea is

hypotonic, it is the replacement of fluid lost with an even more hypotonic fluid such

as the sports drink or tap water that causes hyponatremia in patients such as Q.B.

37,40

Q.B.’s diarrhea probably caused loss of potassium and bicarbonate through the GI

tract, resulting in hypokalemia and hyperchloremic metabolic acidosis. The

potassium depletion can sensitize ADH secretion in response to hypovolemic stimuli,

and the hypokalemia can also lead to hyponatremia.

37 The cellular efflux of potassium

causes cellular uptake of sodium, further reducing the serum sodium concentration.

CASE 27-5, QUESTION 2: How should Q.B.’s hyponatremia be treated?

The treatment of hypovolemic hyponatremia involves sodium replacement to

correct the deficit. The sodium deficit can be estimated by the following formula:

Recall that TBW = 0.6 L/kg × weight in kg for men and 0.5 L/kg × weight in kg for

women.

Approximately one-third of the deficit can be replaced over the course of the first

12 hours at a rate of less than 0.5 mEq/L/hour. The remaining amounts can be

administered over the course of the next several days.

The use of isotonic sodium chloride solution is ideal for the treatment of

hyponatremia associated with volume depletion. As renal perfusion is restored, free

water will be excreted with appropriate retention of sodium.

40 Because Q.B. has only

mild volume depletion, oral replacement fluids can be given. Oral solutions

containing both electrolyte and glucose

46 or rice-based solutions

47 are ideal for the

management of persistent fluid loss. Glucose not only provides calories but also

promotes the intestinal absorption of ingested sodium.

48 Because the rice-based

solution provides more glucose and amino acids, both of which can promote

intestinal sodium absorption, it is more effective than glucose alone.

2,48

In patients with renal salt wasting, the ongoing daily sodium loss should also be

taken into consideration when estimating the amount of replacement. Potassium

should be given to correct hypokalemia, thereby reducing the hyponatremia as well.

The serum sodium concentration may rise faster than expected because as tissue

perfusion is restored, sodium delivery to the distal tubules will increase and ADH

secretion will be suppressed appropriately.

34,37,40

In the absence of ADH, increased

free-water excretion will improve the serum sodium concentration faster than

initially estimated.

Hypervolemic Hypotonic Hyponatremia

CASE 27-6

QUESTION 1: T.W., a 55-year-old man with a longstanding history of alcoholic liver cirrhosis, is admitted to

the hospital for worsening shortness of breath. His medical history includes portal hypertension, esophageal

varices, and noncompliance with dietary restriction and medications. His BP is 120/60 mm Hg; pulse, 100

beats/minute; RR, 20 breaths/minute. He is afebrile. Physical examination reveals a jaundiced man in

respiratory distress. His jugular vein is flat and lung examination reveals bilateral basal rales. Abdominal

examination shows tense ascites with hepatomegaly and spider angiomas (telangiectasias resembling a spider).

He has 1+ pedal edema bilaterally. Laboratory data on admission are as follows:

Na, 127 mEq/L

K, 3.4 mEq/L

Cl, 95 mEq/L

Total CO2

content, 24 mEq/L

BUN, 10 mg/dL

Serum creatinine (SCr), 1.2 mg/dL

Albumin, 2.5 g/dL

Urine Na, <10 mEq/L

Osmolality, 380 mOsm/L

Identify the possible causes of hyponatremia in T.W. and discuss its pathophysiology. How should he be

treated?

p. 576

p. 577

T.W. had no history of vomiting or diarrhea and had stopped using diuretics before

admission. The physical findings of ascites and bilateral edema are not consistent

with volume depletion but indicate a sodium-excess state. Both sodium and water

retention occur, but the disproportionate accumulation of ingested water relative to

sodium leads to hyponatremia.

34,37,40

Cirrhotic patients who are susceptible to developing hyponatremia have a

decreased effective arterial blood volume.

24,37,46,47 The low urinary sodium

concentration suggests that the effective arterial blood volume was decreased.

15 The

high urinary osmolality in the face of hypotonic hyponatremia suggests, however, that

the release of ADH has been stimulated, impairing free-water excretion. Peripheral

vasodilation causes decreases in systemic arterial BP despite a normal-to-high

cardiac output. This, along with splanchnic venous pooling and decreased oncotic

pressure secondary to hypoalbuminemia, decreases renal perfusion in patients with

cirrhosis, such as T.W.

22,28,46 Decreased renal perfusion activates the renin–

angiotensin–aldosterone system, the sympathetic nervous system, and the release of

ADH. Reabsorption of sodium and water in the proximal tubules is enhanced,

diminishing sodium and water delivery to the distal segments of the nephron. The

diluting capacity of the kidney is thus impaired. Increased secretion of antidiuretic

hormone also promotes free-water reabsorption at the collecting tubule and

contributes to the hyperosmolality of urine and hyponatremia. The hypervolemic

hyponatremia is also seen in patients with heart failure (HF) and nephrotic

syndrome

24–28 and in patients with chronic renal disease who drink excessive amounts

of water

37,40

(see Chapter 14, Heart Failure). As the GFR decreases, distal delivery

of sodium is reduced and the ability to generate free water is impaired. In addition,

the capacity to conserve sodium is impaired in these patients.