Fluid and Electrolytes

Chapter 4 Fluid and Electrolytes

Thomas A. Brown, MD, Sonali J. Shah

Insider’s Guide to Fluid and Electrolytes for The USMLE Step 1

Many of the important concepts that were touched upon in Chapter 3 are further explored in Chapters 4 and 5, on fluid and electrolytes and acid-base balance, respectively. Concepts relating to fluid and electrolytes make up a large portion of the renal physiology and pharmacology material tested on Step 1. You will soon see that this is not a section that requires memorizing lots of small details. Instead, it demands a thorough understanding of the mechanisms of action of various hormones and drugs involved in regulating fluid and electrolyte balance. Know which segments of the nephron are affected by these individual hormones and drugs. If applicable, it is a good idea to categorize how each hormone or drug affects glomerular filtration rate (GFR), renal plasma flow (RPF), filtration fraction, etc. For those of you who do not have a strong background in renal physiology, you may need to read through the discussion in this chapter a few times to fully grasp all of the material.

Basic concepts—renal filtration and transport processes

1 What forces govern the glomerular filtration rate at the level of the glomerulus?

These forces are the same forces that affect fluid movement in the systemic capillaries. Forces that drive fluid across the glomerular membrane include the hydrostatic pressure in the glomerular capillaries and the oncotic pressure in Bowman’s space (Fig. 4-1). Because there is usually very little protein in Bowman’s space, the contribution from the filtrate’s oncotic pressure is typically negligible. Forces that oppose fluid movement across the glomerular membrane are the hydrostatic pressure in Bowman’s space and the plasma oncotic pressure.

Figure 4-1 Summary of forces causing filtration by the glomerular capillaries. The values shown are estimates for healthy humans.

(From Guyton AC, Hall JE: Textbook of Medical Physiology, 11th ed. Philadelphia, WB Saunders, 2007.)

Glomerular hydrostatic pressure and, in turn, glomerular filtration rate (GFR), is altered by constriction or dilation of the afferent and efferent arterioles. Because the glomerulus is located between the afferent and efferent arterioles, changes in the caliber of the arterioles tend to have opposite effects on the glomerulus. Either dilation of the afferent arteriole or constriction of the efferent arteriole will increase glomerular pressure and filtration. Likewise, constriction of the afferent arteriole or dilation of the efferent arteriole will decrease glomerular pressure and GFR.

Note: Most circulating vasoconstricting and vasodilating agents act on the afferent arteriole. An important exception, however, is angiotensin II, which acts preferentially to vasoconstrict the efferent arteriole. Thus, angiotensin II works to preserve GFR in a setting of decreased renal perfusion. Angiotensin-converting enzyme (ACE) inhibitors decrease GFR by inhibiting the formation of angiotensin II on the efferent arteriole (see question 2).

In addition to the oncotic and hydrostatic pressures, the surface area and integrity of the glomerular membranes are also important determinants of GFR. Mathematically, these factors are represented through a filtration constant. These factors are most relevant in disease states in which the glomeruli are damaged. The formula for calculating GFR is given in Chapter 3.

2 How do angiotensin-converting enzyme inhibitors and angiotensin receptor blockers affect glomerular filtration rate?

ACE inhibitors and angiotensin receptor blockers (ARBs) tend to decrease GFR acutely. Blocking the action of angiotensin II results in vasodilation of the efferent arteriole, which decreases intraglomerular pressure and, in turn, decreases filtration.

Although ACE inhibitors and ARBs usually produce a decrease in GFR (manifesting as an increase in plasma creatinine) in the short term, they have an important beneficial effect on preserving renal function in individuals with diabetes and other chronic kidney diseases. This benefit likely results from the fact that a decrease in glomerular pressure, despite acutely decreasing GFR, may over the long term decrease the “wear” on the glomeruli. Because of this benefit, a certain degree of creatinine elevation is tolerated when starting an ACE inhibitor or ARB.

3 What is meant by the term filtration fraction and how will increasing the glomerular capillary oncotic pressure (without changing anything else) affect the filtration fraction?

The filtration fraction is the percent of plasma passing through the glomerular capillaries that is actually filtered by the glomerulus. It can be calculated as shown here:

Normally, this fraction is about 20%. Because the glomerular capillary oncotic pressure opposes filtration, increasing it will decrease the net filtration pressure and decrease the filtration fraction.

4 What are the three layers of the glomerular “filter” and how do they contribute to the process of renal filtration at the glomerulus?

The three components of the glomerular filter include the endothelial cells of the glomerular capillaries, the underlying basement membrane, and the glomerular epithelial cells. These components all contribute to renal filtration in distinct ways.

The endothelium of the glomerular capillaries is fenestrated. Along with the high hydrostatic pressure present in the glomerular capillaries, the fenestration of these capillaries allows for the filtration of large volumes of plasma across the capillary bed.

The underlying basement membrane is negatively charged, which helps prevent filtration (and subsequent loss in the urine) of large negatively charged plasma proteins. Importantly, these negatively charged proteins include albumin, which is why loss of albumin and hypoalbuminemia can occur in various types of glomerular disease (particularly in nephrotic syndromes).

The glomerular epithelial cells or podocytes compose the final layer of the glomerular filter. These specialized cells have cytoplasmic extensions called foot processes, with intervening slit-pores, that together envelop the glomerular capillaries and form a final barrier for filterable molecules to traverse prior to entering the capsular space of the glomerulus.

Note: The glomerulus also contains macrophage-like mesangial cells and mesangial matrix interspersed between these layers (Fig. 4-2). The function of the mesangium is not very well understood (though it may serve both a structural role and a housekeeping role). Regardless, the mesangium can be an important site of glomerular disease.

Figure 4-2 A, Low-power electron micrograph of renal glomerulus. CL, capillary lumen; END, endothelium; EP, visceral epithelial cells with foot processes; MES, mesangium. B, Schematic representation of a glomerular lobe.

(Courtesy of Dr. Vicki Kelley, Brigham and Women’s Hospital, Boston, MA.)

5 What is the significance of the creatinine clearance and how is it measured?

The clearance of any substance is defined as the volume of plasma that is “cleared” of that substance per unit of time. For example, a creatinine clearance rate of 125 mL/min implies that, every minute, creatinine is being completely removed and excreted (by the kidneys) from 125 mL of plasma. As shown by the following equation, the clearance of a substance can be calculated by dividing the rate of urinary excretion of a substance by the substance’s plasma concentration. The rate of urinary excretion of a substance can be determined from its concentration in urine and the urine flow rate.

You can easily derive this formula by recalling that all creatinine that appears in the urine is a result of the removal of creatinine from plasma:

Because creatinine is (for the most part) neither reabsorbed nor secreted, its clearance rate very closely approximates the actual GFR, and it is therefore an important indicator of renal function.

Clinically, a single plasma creatinine level is frequently used, along with a patient’s weight, age, and gender (and in some equations, race and serum albumin as a measure of nutrition status), to estimate creatinine clearance and GFR. These additional factors are included to estimate the rate of creatinine production, which depends on one’s muscle mass (creatinine is a byproduct of the muscle energy storage molecule creatine). Note that these equations (such as the Cockroft-Gault equation and the more sophisticated modification of diet in renal disease [MDRD] equation)work well only when the patient’s renal function is at a steady state. They work poorly when it is rapidly changing, as in acute renal failure.

Summary Box: General Concepts in Renal Filtration and Transport Processes

The determinants of glomerular filtration rate (GFR) include the hydrostatic and oncotic pressures within the glomerular capillaries, the hydrostatic and oncotic pressures of Bowman’s space, and the collective glomerular surface area and integrity (i.e., filtration constant).

The hydrostatic pressure within the glomerular capillaries is regulated by vasoconstriction and vasodilation of the efferent and afferent arterioles.

Most circulating vasoactive substances act to constrict or dilate the afferent arteriole. Angiotensin II is unique in that it acts primarily to constrict the efferent arteriole.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) may acutely decrease GFR, but their effect on lowering glomerular pressure helps preserve renal function over the long term in patients with chronic kidney disease.

The three components of the glomerular filter are (1) the capillary endothelial cells, (2) the basement membrane, and (3) the epithelial cells, or podocytes, and the intervening mesangium.

Creatinine clearance is an important indicator of GFR. Clinically, it is usually estimated from a single measurement of serum creatinine concentration. However, recall that numerous variables (e.g. age, gender, muscle mass) can affect the creatinine concentration.

Estimates of creatinine clearance are inaccurate in the setting of a rapidly changing GFR (i.e., acute renal failure).

Basic concepts—renal control of acid-base balance

1 Why is net renal acid excretion necessary to maintain acid-base homeostasis?

Daily metabolism generates a large quantity of nonvolatile acids (e.g., lactate, sulfate, phosphate) that cannot be excreted by the lungs. These nonvolatile acids must be excreted by the kidneys to prevent the development of a metabolic acidosis.

Nonvolatile acids are derived primarily from the metabolism of dietary proteins in meat and other foods. In contrast, metabolic breakdown of carbohydrates and fats yields largely carbon dioxide, which is easily excreted by the lungs. Vegetarians, for example, typically generate less dietary acid for their kidneys to excrete and, as a result, on average tend to have less acidic urine.

2 What mechanisms does the kidney use to maintain acid-base balance despite this acid load?

In general, the kidney acts to prevent acidosis from developing by secreting acid into the urine while reabsorbing base.

More specifically, the kidneys (1) efficiently reabsorb filtered bicarbonate in the proximal tubule (through a mechanism that is coupled with hydrogen ion secretion into the tubular fluid), (2) synthesize de novo both bicarbonate () to be retained and the acid ammonium () to be secreted, (3) secrete titratable buffers such as ammonia and phosphate (which bind hydrogen ions and increase the acid excretory capacity of the urine without causing a precipitous drop in urinary pH), and (4) actively pump acid (in the form of hydrogen ions) into the tubular fluid at the distal tubule.

3 How do the kidneys reabsorb filtered bicarbonate?

Hydrogen ions that are secreted into the lumen of the proximal tubule (primarily via countertransport with Na⁺) react with bicarbonate in the filtrate to form carbonic acid, which rapidly dissociates into carbon dioxide and water, both of which can then diffuse back into the cell (Fig. 4-3). In the cell, the reverse reaction takes place. Thus, carbon dioxide reacts with water to generate bicarbonate and a proton (hydrogen ion). The bicarbonate is ultimately returned to the venous circulation, whereas the hydrogen ion is secreted back into the tubular lumen.

Figure 4-3 Proximal tubule.

(From Goldman L, Ausiello D: Cecil Textbook of Medicine, 22nd ed. Philadelphia, WB Saunders, 2004.)

4 What effect does the diuretic acetazolamide have on the acid-base balance of the body? In what clinical conditions might it be used?

Acetazolamide is an inhibitor of carbonic anhydrase, an enzyme present in the proximal tubule of the nephron (the enzyme is actually anchored to the luminal surface of the plasma membrane of tubular epithelial cells). This enzyme normally catalyzes the rapid dissociation of carbonic acid in the tubular fluid into CO₂ and H₂O, an essential step in the reabsorption of bicarbonate (as described previously). The net effect, therefore, of inhibiting carbonic anhydrase is increased urinary excretion of bicarbonate. Because this negatively charged bicarbonate must be excreted with some accompanying sodium, acetazolamide is also a diuretic (albeit a weak one).

This pharmacotherapeutic mechanism of action essentially mimics the pathophysiology seen in proximal (type II) renal tubular acidoses, in which bicarbonate reabsorption by the tubular epithelium is impaired. The result of decreased bicarbonate reabsorption is a mild metabolic acidosis. This ability of acetazolamide to create a metabolic acidosis can be utilized therapeutically in the treatment or prevention of respiratory alkaloses that develop at elevated altitudes (i.e., mountain sickness). It is also useful to treat conditions such as cystinuria (alkalinizes urine to prevent stone formation) and glaucoma (decreases aqueous humor secretion).

5 How are bicarbonate and ammonium generated de novo by the kidney?

The deamination of glutamine in the proximal tubule generates two ammonium () molecules and two bicarbonate () molecules. The ammonium molecules (which essentially consist of acidic protons being carried by ammonia) are secreted into the tubular lumen, whereas the basic bicarbonate molecules are reabsorbed into the systemic circulation (Fig. 4-4).

Figure 4-4 Production and secretion of ammonium ion () by proximal tubular cells. Glutamine is metabolized in the cell yielding and bicarbonate. The is actively secreted into the lumen by means of a sodium- pump. For each glutamine molecule metabolized, two are produced and secreted and two are returned to the blood.

(From Guyton AC, Hall JE: Textbook of Medical Physiology, 11th ed. Philadelphia, WB Saunders, 2007.)

Glutamine deamination is stimulated by increased levels of H⁺ ions or CO₂ within the cells of the proximal tubule. Thus, this mechanism appropriately increases the renal synthesis of bicarbonate (to be retained) and ammonium (to be secreted) in acidotic conditions.

Summary Box: Renal Control of Acid-Base Balance

Metabolism generates a large quantity of nonvolatile acids that must be excreted by the kidneys. This is accomplished by several mechanisms:

The reabsorption of filtered bicarbonate in the proximal tubule via a mechanism requiring the activity of carbonic anhydrase

The de novo synthesis of bicarbonate (to be retained) and ammonium (to be secreted)

The secretion of titratable buffers (e.g., ammonia, phosphate to increase the acid-carrying capacity of urine)

The secretion of acid via a proton pump in the distal tubule

For more information on the regulation of acid-base balance, see Chapter 5.

Basic concepts—renal control of extracellular fluid balance

1 What are the extracellular fluid compartments of the body and how do their relative sizes compare to the intracellular fluid compartment?

The extracellular fluid (ECF) consists of the interstitial fluid and plasma.

Overall, total body water in a healthy young man is roughly 60% of body weight (whereas in a female subject it is about 50%). For an “average” 70-kg man, total body water is 42 L (recall that 1 L of water weighs 1 kg). About two thirds of the total body water is found within cells; the other one third makes up the ECF volume. Thus, a 70-kg man has about 14 L of ECF: (70 × 0.6) × 1/3. Plasma volume accounts for about one third to one fourth of the ECF (about 4 L or so in a 70-kg individual), whereas the rest is interstitial fluid.

2 How do the kidneys regulate extracellular fluid volume?

The kidneys regulate ECF volume by adjusting the rate of excretion of sodium. In contrast, the kidneys regulate body fluid osmolarity and sodium concentration by altering the excretion of free water (water without sodium). This is one of the most important concepts in renal physiology: In the normal state, volume is regulated through sodium balance, whereas osmolarity and sodium concentration are regulated through water balance.

To be more precise, it is effective circulating volume (or ECV) that is regulated by the body, not the ECF volume. This is because the body has no way to directly follow ECF volume levels. Instead, various pressure and volume detectors located throughout the circulatory system (in the atria, the aortic arch, the carotid sinus, and the afferent arterioles of the kidney) monitor the ECV and, through various mechanisms, stimulate or inhibit Na⁺ excretion. ECV is not a measurable volume. It refers to the volume of arterial blood effectively perfusing tissue. ECV is generally proportional to ECF, but notable exceptions occur during congestive heart failure (CHF), cirrhosis, and nephrotic syndrome.

The renin-angiotensin-aldosterone system (RAAS) is possibly the most important of these mechanisms.

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Apr 7, 2017 | Posted by admin in NURSING | Comments Off

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