Chapter 6: Renal Physiology and Acid-Base Balance

Overview

The kidney is a homeostatic organ that varies the excretion of water, electrolytes, and other hydrophilic molecules to maintain constancy of the composition of the extracellular fluid (ECF). This organ plays the most important role in the long-term regulation of blood pressure through its control of ECF volume. The kidney is also the major effector that varies excretion of metabolic acids and many electrolytes, including K⁺, Ca²⁺, and Mg²⁺.

Anatomy of the Kidney

The paired kidneys are bean-shaped retroperitoneal organs, each about 12-cm long and located on the posterior abdominal wall. Figure 6-1 shows the structures that pass through the renal hilus, including the renal artery, the renal vein, and the renal pelvis (the renal nerves and lymphatic vessels are associated with the renal blood vessels). The cut surface of the kidney has a pale outer region, the cortex, and a darker inner region, the medulla. The medulla is further divided into several conical areas called renal pyramids. The apex of each pyramid tapers toward the renal pelvis, forming the renal papillae. The renal pelvis has a funnel-shaped upper end and is continuous with the ureter below it, which conveys urine to the bladder.

Renal colic is pain in the flank that radiates toward the groin. Colicky pain is pain that comes and goes and is often accompanied by nausea, vomiting, diaphoresis, and hematuria. Renal colic occurs with sudden acute onset and is often severely painful. The most common cause of renal colic is renal calculi (“kidney stones”), which make their way from the renal pelvis down the ureter to the bladder. The three common sites of obstruction leading to the clinical presentation of renal colic are:

1. At the junction of the renal pelvis and ureter.

2. At the site where the ureter passes over the pelvic brim.

3. At the uterovesicular junction.

Papillary necrosis is another condition that can result in renal colic. Necrosis of the renal papillae is associated with the use of analgesics (e.g., nonsteroidal anti-inflammatory drugs). The necrotic papillae can slough off, resulting in obstruction and symptoms of renal colic.

Structure of the Nephron

The functional unit of the kidney is a nephron, a tube that consists of different transporting epithelia in sequence. Each kidney has between 500,000 and 800,000 nephrons. A nephron has several functionally and histologically distinct segments (Figure 6-2). The glomerulus is the site of primary urine formation where blood plasma is filtered into the nephron. The glomerular capillaries are enveloped by the blind-ended upper part of the nephron, known as Bowman's capsule. Filtrate flows from Bowman's space into the proximal tubule, which consists of convoluted and straight portions. The proximal tubule is continuous with the loop of Henle, which is a U-shaped tubule that descends variable distances into the medulla before turning back toward the cortex. The loop of Henle has three functionally distinct parts: the thin descending limb, the thin ascending limb, and the thick ascending limb. The macula densa is a short segment that passes close to the glomerulus and connects the thick ascending limb to the distal tubule in the cortex. Distal tubules from approximately six nephrons converge with a single collecting duct. As the collecting ducts descend through the renal medulla, toward the papilla, they converge to form the larger ducts of Bellini, which deliver final urine into the renal calyces. Urine proceeds to the renal pelvis and then to the lower urinary tract.

Types of Nephrons

There are two types of nephrons: about 85% are cortical nephrons and 15% are juxtamedullary nephrons (Figure 6-3). The glomeruli of cortical nephrons are located in the outer cortex and the loops of Henle are short. In contrast, the juxtamedullary nephrons have glomeruli located deep in the cortex and the loops of Henle are long, with many extending all the way to the tip of the renal papilla. The juxtamedullary nephrons are important for urine concentration. They also reabsorb a higher proportion of glomerular filtrate than cortical nephrons and are said to be “salt-conserving.” In states where effective circulating blood volume is reduced, a higher proportion of renal blood flow (RBF) is directed to the juxtamedullary nephrons, helping to conserve extracellular fluid volume.

General Principles of Urine Formation

Urine formation begins with glomerular filtration of plasma at a rate of about 150–200 L daily. The glomerular filtration rate (GFR) is a controlled variable and in most circumstances is fairly constant (see Chapter 1). Renal insufficiency occurs when GFR is low, however. A progressive decline in GFR indicates the stages of chronic kidney disease as mild (60–89 mL/min/1.73m­²), moderate (30–59 mL/min/1.73m­²), and severe (15–29 mL/min/1.73m­²).

Glomerular filtrate is modified by epithelial transport as it flows along the nephron. For water and many solutes, 98–99% of the filtrate is reabsorbed back into the blood during passage along the renal tubules. A variation of excretion rates in final urine usually reflects changes in renal tubular reabsorption. The rate of reabsorption for most substances is highest in the proximal tubule and is reduced as the flow becomes more distal. Fine control of excretion usually occurs in the distal parts of the renal tubule, which receive a fairly constant fraction of the filtrate (about 10%). The model of filtration–reabsorption applies to most substances. For others, such as K⁺, H⁺, and some organic molecules, the rate of secretion into the urine across the nephron epithelia is more important than reabsorption in determining the excretion rate. Figure 6-4 illustrates these general principles of urine formation.

Penicillin is an antibiotic that is both filtered at the glomerulus and secreted into the tubular urine by the proximal tubule. The secretion of penicillin can be inhibited by the drug probenecid, which can be given concomitantly to reduce the rate of penicillin excretion and thereby to increase serum penicillin levels.

Renal Blood Flow

The kidneys normally receive 20–25% of cardiac output; a very high rate of RBF is needed to supply enough plasma for glomerular filtration. RBF is usually autoregulated across a wide range of mean arterial blood pressures, which helps to maintain a stable GFR. RBF can be reduced by sympathetic vasoconstriction if extracellular fluid volume must be conserved. All blood entering the kidney passes through larger branches of the renal artery to reach the glomerular capillaries in the renal cortex. Figure 6-4 shows the pathway of blood flow through the renal microvasculature. There are several important features in the organization of the renal microcirculation:

1. The glomerular capillary bed is supplied by an afferent arteriole and drained via an efferent arteriole rather than by a venule. A resistance vessel at each end of the glomerular capillary maintains the large capillary blood pressure that drives filtration.

2. The peritubular capillary bed surrounding the nephrons receives reabsorbed water and solutes; it is supplied from the efferent arterioles and is in series with the glomerular capillaries. Filtration of protein-free fluid from the glomerular capillaries increases the osmolarity of blood entering the peritubular capillaries. This provides a driving force to assist in water reabsorption into the peritubular capillaries from the nephron.

3. Some of the peritubular capillaries give off long capillary loops called vasa recta, which travel with the loops of Henle and are involved in the urine-concentrating mechanism. Less than 10% of RBF follows a course through the vasa recta to the renal medulla and only about 1% reaches the renal papilla. Low blood flow in the renal medulla helps to preserve the medullary hypertonicity necessary for the concentration of urine but causes it to be susceptible to ischemia in the setting of hypotension or renal vasoconstriction.

Renal perfusion is achieved with a typical systemic arterial perfusion pressure of about 90–100 mm Hg. High rates of RBF are possible because renal vascular resistance is low. Figure 6-5 shows sites of pressure decreases between the renal artery and vein. The large pressure decreases across the afferent and efferent arterioles demonstrate that vascular resistance is shared somewhat equally between the arterioles. There is very little pressure decrease in the glomerular capillaries, facilitating glomerular filtration.

The normally high rates of renal perfusion provide a large excess of O₂ for tissue metabolism. However, the kidney is readily injured in states of shock, where RBF decreases because renal tissue has a high rate of O₂ use. Persistently low renal perfusion may result in acute renal failure (ARF).

The terms ARF versus chronic renal failure merely describe a different time course.

• ARF is defined as a decrease in GFR that occurs over hours to days.

• Chronic renal failure is present if GFR remains impaired for more than 3 months.

ARF is often asymptomatic and completely reversible and incorporates a vast array of conditions and diseases. For diagnostic and management purposes, ARF is organized into the following three categories:

1. Prerenal ARF is most common and is caused by any condition that results in renal hypoperfusion without impairing the renal parenchyma (e.g., hypovolemia).

2. Renal ARF describes diseases that directly result in damage to the renal parenchyma (e.g., glomerular nephritis).

3. Postrenal ARF occurs in diseases that cause obstruction of the urinary tract (e.g., tumors or benign prostatic hyperplasia).

(Note: severe prerenal ARF can progress to renal ARF if hypoperfusion is severe enough to cause ischemic injury to the renal parenchyma. This results in acute tubular necrosis, which is the most common cause of renal ARF.)

Endocrine Functions of the Kidney

The kidney is a target organ for several hormones, including antidiuretic hormone (ADH), angiotensin II, aldosterone, atrial natriuretic peptide (ANP), and parathyroid hormone (PTH). The kidney is also an endocrine organ that secretes renin, erythropoietin (EPO), and the active form of vitamin D₃, 1,25-dihydroxycholecalciferol (1,25-(OH)₂ vitamin D).

Renin Secretion

Renin is an enzyme released by the juxtaglomerular apparatus of the kidney in response to a decrease in effective circulating blood volume. Figure 6-6 shows the juxtaglomerular apparatus, which is formed from the close association between the vascular and tubular structures where the distal nephron comes in contact with its own glomerulus. Renin is released from the juxtaglomerular cells lining the afferent arterioles, which respond to reduced renal perfusion, and initiates a cascade of events that result in the production of the hormones angiotensin II and aldosterone (see Chapter 8). The renin-angiotensin-aldosterone system is the most important endocrine axis in control of the extracellular fluid volume. A second key regulatory function of the juxtaglomerular apparatus is the feedback regulation of GFR resulting from interaction between the macula densa and the afferent arteriole (see Tubuloglomerular Feedback).

EPO Secretion

EPO is a glycoprotein hormone produced by fibroblasts in the renal interstitium. Local PO₂ in renal tissue is used as an indicator of the systemic arterial O₂ content. EPO is released in response to low renal interstitial Po₂. It stimulates red blood cell formation in the bone marrow to restore the O₂-carrying capacity of blood (Figure 6-7). About 80% of plasma EPO is produced in the kidney and the remainder is secreted by the liver. The mechanism coupling low Po₂ to EPO secretion involves increased local production of prostaglandins. Patients with renal failure do not secrete sufficient amounts of EPO and, therefore, they usually develop anemia.

Clinically, the main uses of EPO are related to treating anemia associated with chronic renal failure or to cancer chemotherapy. However, EPO has also gained notoriety in the lay press as a “blood-doping” agent that is used illegally by endurance athletes. In healthy individuals, injection of EPO will lead to supraphysiologic levels of red blood cells (increased hematocrit) and consequently an increase in O₂-carrying capacity, a result that boosts aerobic output in athletes during competition.

Activation of Vitamin D

Vitamin D is a steroid derived from precursors that are either ingested or produced by the action of ultraviolet light on the skin. The active form of vitamin D is 1,25-dihydroxycholecalciferol (1,25-(OH)₂ vitamin D). The liver produces 25-hydroxycholecalciferol (25-OH vitamin D), which is converted to 1,25-(OH)₂ vitamin D in the kidney under the control of parathyroid hormone. Vitamin D₃ promotes Ca²⁺ conservation in the body by increasing intestinal Ca²⁺ absorption and also by reducing urinary Ca²⁺ loss (Figure 6-8).

Manifestations of chronic renal failure plague many of the body's systems, including bone. Osteitis fibrosa cystica (renal osteodystrophy) is the classic bone disease related to chronic renal failure. The pathophysiologic cascade begins in the kidneys and ends in the bones:

1. As the kidneys fail, so does the function of 1α-hydroxylase, the enzyme that converts inactive 25-OH vitamin D to active 1,25-OH vitamin D, resulting in vitamin D deficiency.

2. Vitamin D deficiency results in low serum Ca²⁺ due to impaired dietary absorption.

3. Low serum Ca²⁺ stimulates the parathyroid glands to increase PTH production (secondary hyperparathyroidism) (see Chapter 8).

4. PTH acts on bone to cause a high rate of bone turnover, which releases Ca²⁺ back into the serum.

The end result of this cascade is that near normal plasma Ca²⁺ concentration is maintained at the expense of chronic bone resorption resulting from hyperparathyroidism. Osteitis fibrosa cystica is a condition characterized by fibrous replacement of the marrow and cystic trabecular bone, which renders the bones fragile and, therefore, increases the risk of fracture.

A large GFR provides the potential to excrete multiple solutes that may be present at low concentrations in plasma. The glomerular filter should not allow passage of blood cells or plasma proteins. Starling's forces are responsible for the net filtration pressure across the glomerular capillaries. GFR is generally stable due to autoregulation but can be varied by active changes in afferent and efferent arteriolar tone.

The term glomerulonephritis is used to denote glomerular injury. In virtually all cases, GFR is impaired and protein or blood cells can be seen in the urine. Diseases that affect the glomeruli can be classified according to the syndrome of symptoms produced.

• Nephrotic syndrome is characterized by severe proteinuria (>3.5 g/d), hypoalbuminemia (<3 g/L), generalized edema, and hyperlipidemia.

• Nephritic syndrome is characterized by hematuria, hypertension, oliguria (<400 mL/d urine output), and azotemia (increased blood urea nitrogen [BUN] and plasma creatinine concentration).

Glomerular Filtration Barrier

Molecular size and electric charge are two determinants of solute filterability. Substances with a molecular weight of about 10 kDa are freely filtered; as molecular weight increases from 10 kDa to 70 kDa, there is a roughly linear decline in the amount of solute filtered (Figure 6-9A). Albumin, with a molecular weight of 70 kDa, is almost small enough to be filtered. It is essential that albumin is not lost in the urine because the plasma albumin concentration is the largest contributor to plasma oncotic pressure. The electrical charge on a macromolecule also determines its filterability (see Figure 6-9B). There is less filtration of negatively charged macromolecules compared to neutral molecules of the same size. At a physiologic extracellular fluid pH of 7.4, proteins carry net negative charges, which reduce their filtration.

The three anatomic structures that a solute passes through during filtration are described as follows (Figure 6-10):

1. The glomerular capillary endothelial cell layer. The large fenestrations between glomerular capillary endothelial cells only exclude blood cells.

2. The glomerular basement membrane consists of a fiber meshwork and offers significant resistance to the sieving of macromolecules.

3. Podocytes are a layer of specialized epithelial cells that coat the glomerular capillaries. Podocytes bear finger-like projections that interlock around the glomerular capillaries. Narrow filtration that slits between these projections are bridged by a membrane protein called nephrin, which also contributes significantly to the filtration barrier.

Fixed negative charges are present in the basement membrane and the filtration slits, and account for electrical repulsion of negatively charged macromolecules by the filtration barrier.

Loss of nephrin, such as occurs in minimal change disease, allows for selective loss of albumin resulting in a nephrotic syndrome. Minimal change disease (or nil disease) is most common in children. The name is derived from the lack of pathologic findings from a renal biopsy examined by light microscopy.

Determinants of GFR

GFR is the product of the net driving pressure forcing fluid out of glomerular capillaries (P_UF) and the permeability of the filtration barrier (K_f):

P_UF is determined by the balance of Starling's forces acting across the filtration membrane:

Under normal circumstances, protein is not filtered so Π_BS is zero. Equation 6-2 simplifies to a more convenient form in which the sum of pressures that oppose filtration (P_BS and Π_GC) are subtracted from P_GC:

Example

 Calculate the net pressure for glomerular filtration if the average hydrostatic pressure in the glomerular capillary is 58 mm Hg, the oncotic pressure in the glomerular capillary is 32 mm Hg, and the hydrostatic pressure in Bowman's space is 10 mm Hg.

The net ultrafiltration pressure is:

• In this example, P_GC = 58 mm Hg, π_GC = 32 mm Hg, and P_BS = 10 mm Hg:

  

Figure 6-11 shows changes in Starling's forces as blood passes along the glomerular capillary from the afferent arteriole to the efferent arteriole. Hydrostatic pressures in the capillary and in Bowman's space remain almost constant, although hydrostatic pressure at the afferent arteriole must be higher than at the efferent arteriole for blood to flow through the glomerulus. Plasma oncotic pressure increases along the glomerular capillary because fluid is being filtered but protein remains in the blood. The glomerular capillary oncotic pressure may increase enough to prevent further filtration, at which point filtration equilibrium is reached. Plotting glomerular capillary oncotic pressure on top of the hydrostatic pressure in Bowman's space, as shown in Figure 6-11, yields a curve describing the sum of forces that oppose filtration; the yellow area indicates net ultrafiltration pressure.

Afferent and Efferent Arteriolar Resistance

Changes in the afferent or efferent arteriolar tone alter both vascular resistance and the glomerular capillary hydrostatic pressure, resulting in changes in renal blood flow and glomerular filtration. Constriction of either arteriole increases vascular resistance and reduces RBF. Afferent arteriolar constriction also reduces GFR because blood flow into the glomerular capillary decreases, reducing the capillary hydrostatic pressure. In contrast, efferent arteriolar constriction increases outflow resistance from the glomerular capillary, increasing the capillary hydrostatic pressure and GFR. The filtration fraction is the proportion of RBF that is filtered and is normally about 20%. Constriction of the afferent arteriole reduces both the RBF and the GFR, leaving the filtration fraction unchanged. Efferent arteriole constriction reduces RBF but conserves GFR, causing an increase in the filtration fraction.

Changes in the filtration fraction affect the Starling's forces in the peritubular capillary network, which is immediately downstream of the glomerulus. Changes in these physical forces within the peritubular capillaries in turn influence fluid reabsorption from the nephron. This is called glomerulotubular balance. In the case of efferent arteriolar constriction, the filtration fraction increases, causing an increase in the peritubular capillary oncotic pressure and a decrease in the peritubular capillary hydrostatic pressure. This causes more fluid to be reabsorbed from the proximal nephron, which prevents a significant change in fluid delivery to the distal nephron. Selective changes in efferent arteriole tone, therefore, have minimal effect on excretion. In contrast, afferent arteriolar constriction does not change the filtration fraction; therefore, a decrease in GFR translates into reduced fluid delivery to the later portions of the renal tubule. Table 6-1 summarizes the changes to RBF, GFR, and the filtration fraction, which result from an altered arteriolar tone. Norepinephrine, a neurotransmitter released by the sympathetic nerves, preferentially constricts the afferent arteriole and reduces RBF, GFR, and Na⁺ excretion. The hormone angiotensin II preferentially constricts the efferent arteriole, which reduces RBF but maintains GFR.

Renal insufficiency can be caused by commonly used drugs that interfere with renal vascular resistance; for example:

• Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen inhibit prostaglandins, which are the primary endogenous vasodilators of the afferent arteriole. Reduced local prostaglandin levels cause vasoconstriction of the afferent arteriole and a decrease in GFR.

• Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers may cause a decrease in GFR due to vasodilation of the efferent arteriole.

Autoregulation of RBF and GFR

RBF and GFR are autoregulated across a wide range of arterial blood pressures (Figure 6-12) (see Chapter 4). Renal vascular resistance varies in direct proportion to renal arterial pressure so that RBF remains almost constant. Control of afferent arteriolar resistance is the basis of autoregulation and occurs by a myogenic mechanism. If blood flow increases, the wall of the afferent arteriole distends. Stretching vascular smooth muscle causes it to contract, which increases vascular resistance and normalizes blood flow.

The myogenic mechanism is assisted by tubuloglomerular feedback. In every nephron, the macula densa senses changes in GFR by measuring the tubular fluid flow rate. If the tubular fluid flow rate increases, the macula densa signals to the afferent arteriole to contract, thereby reducing GFR and normalizing flow past the macula densa (Figure 6-13). The paracrine signaling molecule that passes from the macula densa to the afferent arteriole is thought to be adenosine or adenosine triphosphate (ATP). The autoregulation mechanism can be overridden by sympathetic vasoconstriction to reduce RBF and GFR; for example, a hemorrhage that is severe enough to reduce the mean arterial blood pressure and to activate the sympathetic nervous system via the baroreceptor reflex (see Chapter 4).

Clearance is defined as the volume of plasma rendered free of a given substance in 1 minute. Clearance is calculated as the ratio of urinary excretion rate to plasma concentration:

Example

 If the plasma [urea] is 0.25 mg/mL, the urinary [urea] is 10 mg/mL, and the urine flow rate is 1 mL/min, calculate the excretion rate and the clearance of urea.

Clearance is a volume of plasma “cleaned” per unit time (mL/min), not the amount of solute excreted in urine per unit time (mg/min). A clearance of 40 mL/min means that 40 mL of plasma is required to supply the urea lost in urine every minute. Although renal clearance can be calculated for any solute, the method is often applied to specific marker molecules as a means of estimating the RBF and GFR.

Using Clearance to Estimate GFR

Inulin clearance can be used to estimate GFR. Inulin is a low-molecular-weight polysaccharide that is small enough to pass freely through the glomerular filtration barrier. Inulin is neither reabsorbed nor secreted by the nephron and cannot be metabolized. As shown in Figure 6-14, the rate of inulin filtration equals the rate of inulin excretion in urine so the volume of plasma cleared per minute equals GFR. Inulin usually is not used clinically because it must be intravenously infused.

Creatinine is a product of muscle metabolism and is a suitable endogenous alternative to inulin. The rate of creatinine production in the body is quite constant because it is a function of muscle mass. Creatinine clearance overestimates GFR by about 10% because, in addition to free filtration, there is some secretion into the proximal tubule. Plasma [creatinine] is determined by the balance between the production rate and the excretion rate. Because the creatinine production rate is constant, and the excretion rate varies with GFR, plasma [creatinine] is a direct index of GFR. When GFR is low, plasma [creatinine] is increased.

Calculation of GFR defines the stages of renal failure. A knowledge of GFR is vital in determining the proper dosage of drugs that are excreted via the kidney, because the half-life of a drug can be significantly increased in the setting of renal failure. Creatinine clearance can be estimated clinically using the Cockcroft-Gault equation:

Using Clearance to Estimate RBF

The principle of clearance can also be used to estimate the renal plasma flow (RPF) rate using the marker para-aminohippuric acid (PAH), which is a derivative of glycine. PAH clearance provides an estimate of the renal plasma flow rate because all of the PAH entering the renal artery is excreted into the urine in a single pass through the kidney. Therefore, the volume of plasma cleared of PAH is the total volume of plasma passing through the kidney per minute. Figure 6-15 illustrates renal PAH handling; at low plasma concentrations, all of the PAH that escapes filtration and enters the peritubular capillaries is secreted by organic anion transporters in the proximal tubule. The term effective renal plasma flow (ERPF) rate is sometimes used to describe PAH clearance, since the measurement relates to plasma flowing to functional nephron units. RBF can be calculated from the RPF rate if the hematocrit is known:

Quantifying Tubular Function

The rate of urinary excretion of a substance can be affected by glomerular filtration, tubular reabsorption, and tubular secretion. Calculations used to quantify tubular transport are summarized in Table 6-2 and are described as follows:

• The amount of a substance filtered per unit time is known as the filtered load.

• The amount excreted per unit time is referred to as the excretion rate.

• The rate of net tubular transport is the difference between the filtered load and the excretion rate. When excretion is less than the filtered load, there is net tubular reabsorption. When the excretion rate is more than the filtered load, there is net tubular secretion. Solutes with net reabsorption have clearance values less than GFR (i.e., less than creatinine clearance). If there is net tubular secretion, solute clearance is greater than GFR.

• Fractional excretion (FE) expresses solute excretion as a percentage of its filtered load. FE is useful because changes reflect altered tubular transport rather than simply changes in GFR. FE is also known as the clearance ratio because it can be calculated as the ratio of solute clearance to creatinine clearance.

Calculating the fractional sodium excretion (FE_Na) can be useful in the setting of acute renal failure (ARF) to help determine if ARF is due to prerenal (hypovolemia) versus renal (acute tubular necrosis) pathology. In the prerenal state, the FE_Na will be low (<1%) as the renal tubules attempt to maintain intravascular volume by maximally reabsorbing Na⁺­ (and water). If ARF is caused by an intrinsic renal process (most commonly acute tubular necrosis), then FE_Na will be large (>2%) due to the reduced ability of the damaged renal tubules to reabsorb Na⁺­. (Note: diuretics interfere with tubular Na⁺­ reabsorption and, therefore, impair the ability to interpret FE_Na. In this setting, FE_urea can be used.)

Relationships Between Clearance and Plasma Concentration

The clearance of a solute may change as a function of plasma concentration if a saturable transport process is involved in its renal handling. Because there are no tubular transport processes for inulin, the filtered load and the excretion rate of inulin increase in parallel with plasma concentration. Clearance is the ratio of excretion rate to plasma concentration; therefore, inulin clearance remains constant at all plasma inulin concentrations. By contrast, PAH clearance decreases with increasing plasma PAH concentration (Figure 6-16). At low plasma PAH concentrations, all PAH is excreted and the PAH clearance represents the RPF rate. As the plasma PAH concentration increases, the tubular secretion mechanism becomes saturated and some PAH remains in the plasma. PAH clearance decreases because not all plasma is now being cleared of PAH. PAH clearance never decreases below GFR because there are no tubular reabsorption mechanisms for PAH.

Tubular glucose transport can be saturated. At normal plasma glucose concentrations, glucose normally is not found in the urine because the filtered glucose load is completely reabsorbed. If the plasma glucose concentration increases (e.g., as occurs in patients with diabetes mellitus), the filtered load of glucose increases and the reabsorption mechanism may be saturated. This explains why glucose is excreted in the urine of diabetic patients when there is poor glycemic control. The glucose clearance can never exceed the inulin clearance because there is no secretion mechanism for glucose.

Renal Titration Curves

Renal titration curves can be used to determine the maximum rate of solute transport (transport maximum, T_m) for solutes with saturable transport. Construction of a titration curve first requires calculation of the filtered solute load for a range of plasma solute concentrations. Excretion rates are measured from urine samples across the same range of plasma solute concentrations. The net tubular transport is calculated from the difference between the filtered load and the excretion rate. The renal titration curve for glucose is shown in Figure 6-17. The plasma solute concentration at which the solute first appears in urine is called the renal threshold. The glucose reabsorption curve levels off gradually rather than reaching the plateau abruptly. This phenomenon is called splay and is due to variability in the tubular transport maxima between nephrons. The plateau of the glucose reabsorption rate at glucose concentrations that saturate the transport mechanism reveals the T_m for glucose.

Some of the presenting symptoms of hyperglycemia in the untreated diabetic patient can be explained by understanding the T_m for glucose as follows:

1. Polyuria. When the T_m for glucose is surpassed as a result of hyperglycemia, glucose (and water) remains in the urine, causing an osmotic diuresis.

2. Polydipsia. The osmotic diuresis from the glucosuria results in free water loss, which increases serum osmolarity, activating osmoreceptors in the hypothalamus, and provoking the sensation of thirst.

3. Hypovolemia. Polyuria and urinary free water loss can cause significant hypovolemia.

The daily filtered load of Na⁺ is far greater than the daily requirement for Na⁺ excretion; Na⁺ balance is achieved with a FE_Na of 1–2%. Filtration and reabsorption are the only significant processes affecting NaCl and water excretion. If it is necessary to reduce the extracellular fluid volume in states such as edema or hypertension, diuretic agents can be given to increase urinary NaCl and water excretion. Most diuretics inhibit tubular Na⁺ reabsorption.

Overview of Segmental Na⁺ Handling

Figure 6-18 summarizes segmental Na⁺ handling. The proximal tubule reabsorbs approximately 65% of filtered Na⁺. The loop of Henle reabsorbs 20–25% of the filtered load, with about 10% of filtered Na⁺ consistently delivered to the distal tubule, independent of dietary salt intake. Final excretion of Na⁺ is determined by variable reabsorption along the distal tubule and the collecting duct. Active Na⁺ reabsorption is the key driving force behind NaCl reabsorption all along the nephron. Cl⁻ reabsorption is passive or occurs via secondary active transport, coupled to the movement of Na⁺. Water reabsorption is coupled to the reabsorption of NaCl and occurs by osmosis.

Proximal Tubule

Na⁺ reabsorption is coupled to the transport of several other solutes in the proximal tubule, including the absorption of nutrients and Cl⁻ and HCO₃⁻. In the early proximal tubule, Na⁺ reabsorption is preferentially coupled to the recovery of filtered nutrients and HCO₃⁻. This reabsorption accounts for the decline in the concentration of these solutes early in the proximal tubule, as shown in Figure 6-19A. In later portions of the proximal tubule, Na⁺ reabsorption is coupled to Cl⁻ reabsorption. The osmolarity of tubular fluid does not change along the proximal tubule because the sum of all solute transport is isosmotic with plasma. The data in Figure 6-19A were obtained after the administration of inulin; the extent of water reabsorption is demonstrated by the large increase in inulin concentration, which becomes concentrated in the lumen as water is reabsorbed.

Figure 6-19B shows mechanisms of cellular Na⁺ uptake in the proximal tubule. Glucose and amino acids are recovered from the glomerular filtrate via Na⁺-linked cotransporters. Nutrient uptake only requires a small proportion of filtered Na⁺, and a much larger amount of Na⁺ is reabsorbed via the Na⁺/H⁺ exchange. Secretion of H⁺ into the lumen is then coupled indirectly to reabsorption of Cl⁻ or HCO₃⁻. Approximately one third of Na⁺ reabsorption in the proximal tubule occurs passively through the intercellular junctions via the paracellular pathway.

Loop of Henle

There is no active Na⁺ transport in the thin limbs of the loop of Henle. In contrast, the thick ascending limb is very metabolically active and Na⁺ uptake occurs via cotransport with Cl⁻ and K⁺ (Figure 6-20). This uptake mechanism is electrically neutral, with 1Na⁺, 2Cl⁻, and 1K⁺ carried across the apical cell membrane during each transport cycle. Na⁺ is pumped out of the cell via the basolateral Na/K-ATPase. Cl⁻ leaves via a Cl⁻ channel in the basolateral membrane, and K⁺ is recycled across the apical membrane via K⁺ channels. The conjunction of an apical K⁺ conductance and basolateral Cl⁻ conductance creates a lumen-positive transepithelial electrical potential difference. This voltage is important because it drives a significant paracellular flux of cations, particularly Ca²⁺ and Mg²⁺. Loop diuretics (e.g., furosemide) induce natriuresis mainly by blocking the Na/2Cl/K cotransporter; the transepithelial electrical potential is also decreased, resulting in the increased urinary loss of divalent cations.

Bartter's syndrome is a salt-wasting disease caused by gene mutations in the Na/2Cl/K cotransporter, the luminal K⁺ channel, or the basolateral Cl⁻ channel in the thick ascending limb. Loss of function in the thick ascending limb causes very large urinary losses of NaCl, reflecting the high proportion of the filtered load normally reabsorbed at this site. There is also urinary wasting of Ca²⁺ and Mg²⁺ due to the loss of the positive transepithelial potential difference in the thick ascending limb.

Distal Tubule and Cortical Collecting Duct

The distal tubule and the cortical collecting duct are important areas for fine regulation of Na⁺ excretion. The hormone aldosterone increases the activity of the Na⁺ transport proteins throughout this area to promote renal Na⁺ conservation and maintain the extracellular fluid volume. In the early distal tubule, NaCl reabsorption is coupled via a Na-Cl cotransporter (Figure 6-21A). Na⁺ exit at the basolateral membrane is via the Na/K-ATPase, and Cl⁻ exit is via the Cl⁻ channel.

The cortical collecting duct has two distinct cell types. The principal cells are the most abundant cells and are associated with NaCl reabsorption; the intercalated cells are involved with acid-base balance. Na⁺ uptake in the principal cells occurs through a Na⁺ channel (see Figure 6-21B). Na⁺ reabsorption is associated with K⁺ secretion through K⁺ channels; Cl⁻ reabsorption occurs passively via the paracellular pathway. The late distal tubule is transitional between the distal convoluted tubule and the cortical collecting duct and expresses both Na-Cl cotransporters and Na⁺ channels. Na⁺/H⁺ exchange occurs all along the distal tubule and the cortical collecting duct and contributes to both Na⁺ uptake and acid excretion. Thiazide diuretics block the Na-Cl cotransporter of the distal tubule (see Diuretics). Unlike loop diuretics, which cause urinary loss of Ca²⁺ by inhibiting Ca²⁺ reabsorption in the thick ascending limb, thiazides reduce urinary calcium loss by increasing Ca²⁺ reabsorption in the distal tubule.

Gitelman's syndrome is a salt-wasting condition caused by gene mutations in the Na-Cl cotransporter expressed in the distal tubule. The extent of salt wasting is milder than occurs in Bartter's syndrome and reflects the lower proportion of the filtered load that is normally reabsorbed in the distal tubule compared to the loop of Henle. Hypocalciuria is a feature of Gitelman's syndrome and is the result of increased Ca²⁺ reabsorption in the distal nephron.

Diuretics

Diuresis is defined as an increase in the urine flow rate; diuretics are agents that induce diuresis. Most diuretics used clinically are organic acids that are efficiently secreted by the proximal tubule; they act by inhibiting various luminal membrane Na⁺ transport proteins. Table 6-3 summarizes common agents, their sites of action, and their uses. Figure 6-22 illustrates sites of action for different classes of diuretics.

Loop diuretics (e.g., furosemide) inhibit the Na/2Cl/K cotransporter in the thick ascending limb. Explosive increases in urine flow occur because this nephron segment normally reabsorbs 20–25% of filtered Na⁺. Because of their powerful diuretic effect, loop diuretics are particularly useful when rapid diuresis is needed (e.g., pulmonary edema).

Thiazide diuretics (e.g., hydrochlorothiazide) inhibit Na-Cl cotransport in the distal tubule. Thiazides are less potent than loop diuretics because a lower proportion of the filtered NaCl load is reabsorbed in the distal tubule compared to the loop of Henle. Thiazides are considered first-line agents in the treatment of hypertension , but they can also be used in a variety of other conditions, including symptomatic relief of edema and hyper calciuria .

Agents that act on the principal cells in the cortical collecting duct are called K⁺-sparing diuretics because inhibition of Na⁺ reabsorption at this site also inhibits K⁺ secretion. Amiloride is an example of this class of diuretic, which acts by blocking apical Na⁺ channels in the principal cells. Aldosterone antagonists (e.g., spironolactone) belong to the group of K⁺-sparing diuretics and act by reducing the expression and activity of Na⁺ transport proteins in the cortical collecting duct.

K⁺-sparing agents have a weak diuretic effect because less than 5% of filtered Na⁺ is reabsorbed at this site. However, agents in this group can be helpful in the treatment of certain specific disorders, including:

• Liddle's syndrome is caused by a genetic mutation that increases the function of the apical Na⁺ channels in the principal cells. Patients have aggressive sodium retention and are at risk of developing salt-sensitive hypertension. The affected Na⁺ channels are the same ones blocked by amiloride, which makes it the drug of choice for treating Liddle's syndrome.

• Primary hyperaldosteronism (Conn's syndrome) most commonly occurs as a result of an aldosterone-secreting adenoma in the adrenal cortex (see Chapter 8). The classic clinical findings are hypertension, hypokalemia, and metabolic alkalosis. In addition to surgery, aldosterone antagonists (e.g., spironolactone) can be helpful in the treatment of Conn's syndrome.

Carbonic anhydrase inhibitors (e.g., acetazolamide) dramatically reduce bicarbonate reabsorption in the early proximal tubule, producing a weak diuresis. Because of their weak diuretic effect, carbonic anhydrase inhibitors are rarely used for this purpose. Acetazolamide is commonly used in the treatment or prophylaxis of altitude sickness and in reducing intraocular pressure associated with glaucoma.

Osmotic diuretics are nonreabsorbed solutes present in the tubule lumen; they cause water to remain in the lumen and to be passed into the urine. An example of osmotic diuresis discussed previously is untreated diabetes mellitus, when the glucose T_m is exceeded and glucose remains in the tubule lumen (see Renal Titration Curves). The proximal tubule and thin descending limb of the loop of Henle are the main sites of action because these areas have the highest membrane water permeability and are affected most by osmotic gradients.

The inert sugar mannitol can be used to clinically induce an osmotic diuresis. Mannitol can be helpful in the treatment of patients with head injuries to reduce intracranial pressure by producing a fluid shift out of the brain.

Body fluid osmolarity remains within narrow limits despite variations in water and solute intake or loss. The ability of the renal system to rapidly vary water excretion over a wide range in response to fluctuations in plasma osmolarity is the main reason that water balance exists. Three processes are required for the renal system to vary urine concentration:

1. Adequate glomerular filtration is needed to deliver NaCl and water to the loop of Henle.

2. Na⁺ reabsorption without water reabsorption in the ascending limb of the loop of Henle dilutes tubular fluid, providing the potential to excrete dilute urine. At the same time, the medullary interstitial fluid becomes hypertonic, providing the potential to concentrate urine in the collecting ducts.

3. Water permeability in the collecting duct must be variable, which is controlled via ADH.

ADH

Variation in water excretion in response to changes in plasma osmolarity is mediated through changes in ADH (vasopressin) secretion. Figure 6-23 shows a close correlation between plasma osmolarity and plasma ADH concentration. The normal set point for plasma osmolarity is 285–288 mOsm/L, which is associated with an ADH concentration of about 2–3 pg/mL. Large increases in ADH secretion occur if osmolarity increases and/or blood volume decreases. The combined effects of ADH at the kidney result in the formation of concentrated urine and retention of solute-free water in the body. ADH is called vasopressin because it is also a potent vasoconstrictor. V₁ receptors mediate vasoconstriction; V₂ receptors mediate renal water retention.

ADH is synthesized in the supraoptic and paraventricular nuclei of the hypothalamus and is secreted from nerve terminals in the posterior pituitary gland (see Chapter 8). ADH secretion is directed by neuronal osmoreceptors in the hypothalamus. A 1% deviation of plasma osmolarity is enough to vary ADH secretion. Reductions in plasma volume of more than 10% are also a potent stimulus for ADH secretion. Increased secretion of ADH in response to low blood volume is sensed by low pressure baroreceptors in the atria and lungs as well as by high pressure carotid baroreceptors. Commonly ingested agents that affect ADH are nicotine, which increases secretion, and ethanol, which inhibits secretion.

Pathologic oversecretion of ADH results in the syndrome of inappropriate antidiuretic hormone (SIADH). SIADH is caused by various clinical conditions, including small cell carcinoma of the lung (most common), pneumonia, or head injury. Continuous ADH secretion leads to retention of solute-free water and eventually to hyponatremia; severe hyponatremia can be fatal. Treatment of SIADH revolves around identifying and treating the underlying condition.

Concentrating or Diluting Urine

An increase in plasma osmolarity results in the excretion of urine that is more concentrated than plasma; some solute-free water is returned to the extracellular fluid, and plasma osmolarity is reduced toward normal. A decrease in plasma osmolarity results in the excretion of urine that is more dilute than plasma; some solute-free water is excreted in the urine, increasing the body fluid osmolarity toward normal. These changes in urine osmolarity can occur without significant changes in GFR or total solute excretion. Whether the kidney produces concentrated or dilute urine depends on ADH levels.

Figure 6-24 compares the segmental osmolarity profile of tubular fluid when there is either a high or a low plasma ADH level. In either case, fluid in the proximal tubule remains isosmotic with respect to plasma and makes no contribution to altering urine osmolarity. In the descending thin limb of the loop of Henle, osmolarity reflects that of the surrounding medullary interstitium. There is always some degree of hypertonicity in the medullary interstitium, with a gradient of increasing osmolarity from the outer to the inner medulla. High ADH levels dramatically increase medullary osmolarity, which is reflected by increasing osmolarity along the descending thin limb of the loop of Henle (Figure 6-24). The ascending limb of the loop of Henle is called the diluting segment because it always reduces the tubular fluid osmolarity; in the ascending limb, NaCl is reabsorbed without water. By the time fluid leaves the loop of Henle, it is hypotonic relative to plasma. When ADH levels are low, the water permeability of the distal nephron and collecting duct is very low. Hypotonic fluid entering the distal nephron remains hypotonic during passage through the collecting duct when ADH is low and dilute urine is being produced. The maximal diluting capacity of the renal system is about five- to tenfold (i.e., urine osmolarity of 30–60 mOsm). In contrast, high ADH levels increase water permeability in the distal tubule and collecting duct. Osmotic water reabsorption into the hypertonic interstitium causes the osmolarity of the tubular fluid to increase along the collecting duct, emerging as concentrated urine.

Countercurrent Multiplication

The ability to concentrate urine depends on the generation of a corticomedullary gradient of increasing interstitial osmolarity. Formation of the corticomedullary gradient relies on the countercurrent arrangement of the descending and ascending limbs of the loop of Henle and their differing transport properties (Figure 6-25). The thin descending limb is characterized by high water permeability and the lack of active transport. Osmolarity of the luminal fluid simply reflects that of the surrounding interstitium. The ascending limb is characterized by very low water permeability. Salt reabsorption into the interstitium occurs in the ascending limb by active transport in the thick ascending limb (Figure 6-25, Step 1) and by diffusion in the salt-permeable thin ascending limb (see below). At any given horizontal level, the osmolarity of fluid in the descending limb and interstitium can be 200 mOsmole/L greater than in the ascending limb. This is known as the single osmotic effect and is due to salt reabsorption from the ascending limb.

Amplification of the single effect in the corticomedullary axis is called countercurrent multiplication (Figure 6-25). About 40% of total osmolarity in the inner medulla is due to the presence of urea. A high ADH level causes the expression of uniporters for urea transport in the collecting duct, accounting for high interstitial urea concentration (Figure 6-25, Step 2). High urea concentration draws water out of the descending limb of the loop of Henle by osmosis (Figure 6-25, Step 3). This concentrates NaCl in the descending limb, creating a diffusion gradient for NaCl to move passively out of the thin ascending limb into the interstitium (Figure 6-25, Step 4). The importance of urea is illustrated in patients with a low protein intake who have a reduced capacity to concentrate their urine because of lower urea levels. Children younger than 1 year have a reduced urine-concentrating ability because of lower urea levels; young children utilize proteins for rapid body growth and as a result do not produce much urea.

Countercurrent Exchange

In most organs, rapid diffusion between the capillary blood and the interstitium results in uniform composition of interstitial fluid. If rapid diffusion occurred in the renal medulla, the osmotic gradient would be dissipated. This does not occur because the vasa recta capillaries have a countercurrent loop configuration that tends to trap solutes in the medulla. As shown in Figure 6-26, blood flowing down the descending vasa recta receives solutes from the interstitium by diffusion and loses water by osmosis. Blood reaching the renal papilla is highly concentrated and, as it flows up the ascending vasa recta, solutes diffuse out and water enters by osmosis. This net effect of retaining high solute concentration in the medulla is known as countercurrent exchange. The countercurrent exchange mechanism depends on low medullary blood flow. In states of low ADH, medullary blood flow increases, causing washout of medullary hypertonicity and reduced urine osmolarity.

Aquaporin 2

Whether final urine is dilute or concentrated depends on water reabsorption in the collecting duct. The change from a water-impermeable to a water-permeable epithelium is controlled by ADH and is due to the insertion of aquaporin 2 (AQP2) water channels in the luminal cell membranes of the principal cells (Figure 6-27). Vesicles containing AQP2 just beneath the luminal membrane are shuttled into the membrane in response to ADH.

Diabetes Insipidus

Patients with diabetes insipidus lack proper control of renal water flux by ADH. Water reabsorption under the control of ADH is called facultative reabsorption and is about 20–25 L/d. Water reabsorption that occurs in the more proximal nephron segments not under ADH control is called obligatory reabsorption. Patients with diabetes insipidus may excrete as much as 20–25 L/d, and may require an equivalent water intake to maintain water balance.

There are two types of diabetes insipidus:

1. Central diabetes insipidus is the inability of the posterior pituitary gland to adequately secrete ADH. This type of diabetes insipidus may occur in patients with pituitary tumors that interfere with ADH secretion, or it may occur as a complication following surgical removal of a pituitary tumor.

2. Nephrogenic diabetes insipidus is failure of the kidney to respond to ADH. It can be caused by drugs such as lithium or by rare genetic mutations in AQP 2 or renal ADH receptors.

Osmolar Clearance and Free Water Clearance

Free water clearance is calculated to determine if the ADH endocrine axis and the renal concentrating mechanism are functioning properly. It is the volume of solute-free water excreted per minute. Osmolar clearance must be calculated to derive free water clearance. Osmolar clearance is the volume of plasma cleared of total solute per minute and is calculated from the general clearance equation:

If urine and plasma osmolarity were equal (U_osm/P_osm = 1), Equation 6-7 would become (C_osm = V), and urine flow rate would represent the volume of plasma cleared of total solute per minute. If the same amount of solute were excreted in dilute urine, a volume of water would be “added” during urine formation, called free water clearance (C_H20):

Therefore, free water clearance is calculated by subtracting C_osm from V. When urine is dilute, C_H2O is a positive number, whereas a negative free water clearance reflects concentration of the urine. Negative free water clearance should be present when a patient has elevated serum ADH levels; otherwise a renal defect is present.

Example

The following data were obtained over a period of several hours from a patient being monitored in the intensive care unit:

• Urine flow rate = 0.1 L/h

• Urine osmolarity = 330 mOsm/L

• Plasma osmolarity = 310 mOsm/L

Calculate free water clearance using the above information and interpret the result, given further information that the patient had a normal increase in the plasma ADH concentration in the setting of this greater than normal plasma osmolarity.

Osmolar clearance must first be calculated to proceed to calculate free water clearance:

Free water clearance:

In the setting of increased plasma osmolarity and increased plasma ADH, the patient is expected to concentrate the urine and therefore to generate a significant negative free water clearance. In this case, free water clearance is near zero, indicating a failure of urine concentration and therefore renal dysfunction.

Long-term control of blood pressure requires maintenance of the normal extracellular fluid volume by the renal system. The vascular function curves presented in Chapter 4 (see Figure 4-32) showed that an increase in the extracellular fluid volume, through increased venous blood volume, will result in increased systemic function pressure (P_SF), increased venous return, increased cardiac output, and high mean arterial pressure. The extracellular fluid volume is a function of the total amount of Na⁺ in extracellular fluid. Regulation of water balance should ensure that increased Na⁺ content results in increased water retention and an increase in extracellular fluid volume. Disorders of extracellular fluid volume (e.g., edema) reflect difficulties with Na⁺ balance, whereas disorders of Na⁺ concentration (i.e., hypernatremia or hyponatremia) indicate difficulties with water balance.

Effective Circulating Volume

Negative feedback control of extracellular fluid volume operates through control of the effective circulating volume, which is related to the volume of blood in the circulation and the pressure within specific parts of the circulation. The kidney is the main effective circulating volume sensor and is well-suited to this role because of the high rate of renal perfusion. The juxtaglomerular apparatus measures changes in the afferent arteriolar wall tension as an index of renal perfusion. If perfusion decreases, there is less stretch of the afferent arteriolar wall, triggering renin release, which in turn activates the angiotensin-aldosterone axis (see Chapter 8). Other sensors of effective circulating volume include arterial baroreceptors and low pressure baroreceptors in the pulmonary system and the cardiac atria. Figure 6-28 shows a negative feedback loop in which changes in effective circulating volume result in altered renal Na⁺ excretion to produce a change in the extracellular fluid Na⁺ content and effective circulating volume. Coupling between changes in the extracellular fluid Na⁺ content and circulating volume occurs via changes in water excretion, which in turn are controlled by ADH. For example, plasma osmolarity increases if more Na⁺ is retained, resulting in ADH release, water retention, and, therefore, in an increase in extracellular fluid volume.

Patients with congestive heart failure have low effective circulating volume because their cardiac performance is poor. Na⁺ and fluid retention result, but effective circulating volume does not improve due to cardiac failure. Instead, edema results as venous and capillary hydrostatic pressures increase. Patients with heart failure continue to retain Na⁺, increasing the extracellular fluid volume without correcting the effective circulating volume, which is why edema is a chronic problem in patients with congestive heart failure. This demonstrates that the effective circulating volume is the controlled physiologic variable, not absolute extracellular fluid volume.

Responses to Low Effective Circulating Volume

A decrease in the effective circulating volume is counteracted in four main ways (Figure 6-29):

1. Activation of the renin-angiotensin-aldosterone axis.

2. Stimulation of the sympathetic nervous system via the baroreceptor reflex.

3. Increased ADH secretion.

4. Increased renal fluid retention via altered Starling's forces in the peritubular capillaries.

The juxtaglomerular apparatus secretes renin in response to reduced renal perfusion, triggering a cascade that increases the serum levels of the hormones angiotensin II and aldosterone. Angiotensin II increases Na⁺ reabsorption from the proximal tubule and causes generalized vasoconstriction to combat arterial hypotension. Angiotensin II supplements the stimulus from low pressure baroreceptors to increase ADH secretion, which increases renal water conservation. Aldosterone from the adrenal cortex acts to increase Na⁺ reabsorption throughout the distal nephron and the cortical collecting duct.

If a decrease in the effective circulating volume is large enough to reduce the mean arterial blood pressure, the baro­receptor reflex activates the sympathetic nervous system. Cardiac output and blood pressure are supported by vasoconstriction and venoconstriction and by increased heart rate and myocardial contractility. Renal sympathetic nerve activation constricts the afferent arterioles, reducing GFR and further stimulating renin release via the β₁ receptors on the juxtaglomerular cells. Norepinephrine also stimulates Na⁺ reabsorption in the proximal tubule.

Low extracellular fluid volume causes a generalized decrease in the capillary hydrostatic pressure. If low effective circulating volume results from a loss of NaCl and water, there is also an increase in the plasma oncotic pressure because serum proteins are concentrated. These subtle changes in Starling's forces promote movement of fluid from the interstitial fluid to plasma. The peritubular capillaries are a site of very high fluid absorption from the renal cortical interstitial fluid to the plasma. Altered Starling forces in low effective circulating volume cause a significant increase in fluid reabsorption into the peritubular capillaries, which promotes fluid reabsorption from the nephron and contributes to renal Na⁺ conservation.

Responses to High Effective Circulating Volume

Figure 6-30 summarizes responses to high effective circulating volume. In persons with normal effective circulating volume and osmolarity, the activity of renin, angiotensin, aldosterone, ADH, and the sympathetic nerves is generally low. This limits the scope for further suppression of these systems when the effective circulating volume increases, and their role is less important than it is during low effective circulating volume. Changes in Starling forces continue to be significant because volume loading increases capillary hydrostatic pressure and decreases oncotic pressure. Reduced fluid reabsorption into the peritubular capillaries allows more fluid to be excreted by the renal tubule.

A high effective circulating volume is also associated with secretion of the hormone ANP, which promotes the loss of Na⁺ and water in urine. ANP is secreted from the cardiac atria in response to greater atrial stretch caused by increased venous blood volume. ANP promotes natriuresis (Na⁺ loss in urine) by increasing GFR and decreasing Na⁺ reabsorption in the collecting duct. ANP also inhibits the secretion of ADH, renin, and aldosterone.

Brain natriuretic peptide is a peptide related to ANP and is named for the location where it was first isolated, the brain. However, it was later found to be produced in the ventricles of the heart. It is thought that the effects of brain natriuretic peptide are similar to ANP, but they may be more potent and longer lasting than the effects of ANP. With the use of recombinant DNA technology, brain natriuretic peptide (nesiritide) has been developed for use in the treatment of patients with congestive heart failure.

Pressure Natriuresis

Increased arterial blood pressure causes increased renal Na⁺ excretion, known as pressure natriuresis, which is expected from the negative feedback control of effective circulating volume (Figure 6-31). However, pressure natriuresis persists in the absence of hormones or renal nerves, showing that there is also intrinsic control of renal Na⁺ excretion in response to altered renal perfusion. Pressure natriuresis occurs in concert with other mechanisms supporting Na⁺ balance and provides a feedback mechanism to maintain normal blood pressure. In patients with hypertension, the pressure natriuresis curve shifts right (Figure 6-31). These patients have insufficient Na⁺ excretion at normal blood pressure. A subset of hypertensive patients are salt sensitive, shown by a pressure-natriuresis curve that has both a right shift and a reduced gradient; in these patients, higher salt intake further increases the blood pressure.

Darrow-Yannet Diagrams

Darrow-Yannet diagrams plot relative changes in the volume (x-axis) and osmolarity (y-axis) of extracellular fluid and intracellular fluid (Figure 6-32). The contraction or the expansion of body fluid volume can occur with low, normal, or high osmolarity. Note that the osmolarities of extracellular fluid and intracellular fluid are always the same at steady state because water moves freely by osmosis between extracellular fluid and intracellular fluid.

Secretory diarrhea (e.g., cholera) and hemorrhage are examples of isosmotic volume contraction. The loss of NaCl from the extracellular fluid in an isosmotic solution causes a decrease in the extracellular fluid volume. There is no change in the osmolarity of extracellular fluid; therefore, there is no osmotic driving force to cause water exchange with intracellular fluid, and intracellular fluid volume is unchanged. The mechanisms previously discussed for low effective circulating volume are activated, but salt and water ingestion or infusion are needed to restore normal conditions.

Sweating is an example of hyperosmotic volume contraction. NaCl is lost from extracellular fluid in a dilute solution, causing the extracellular fluid volume to decrease and the extracellular fluid osmolarity to increase. Water shifts out of intracellular fluid into extracellular fluid by osmosis. At steady state, fluid loss from sweating reduces both extracellular fluid and intracellular fluid volumes, and body fluids have higher osmolarity. Mechanisms to correct low effective circulating volume are activated, particularly ADH secretion in response to high osmolarity.

Adrenocortical insufficiency (e.g., Addison's disease) is an example of hyposmotic volume contraction. Chronic loss of aldosterone results in renal NaCl loss in excess of water loss. Extracellular fluid volume and osmolarity are both reduced. Net water flux from the extracellular fluid into the intracellular fluid is driven by osmosis. At steady state, intracellular fluid volume is increased, and extracellular fluid volume and body fluid osmolarity are reduced. In this pathologic situation, restoration of the normal effective circulating volume is not possible due to the failure of aldosterone secretion. Low effective circulating volume stimulates ADH secretion despite low osmolarity, but the effective circulating volume cannot be restored without renal Na⁺ retention.

Intravenous infusion of 0.9% saline is an example of isosmotic volume expansion of extracellular fluid. There is no change in osmolarity, so there is no fluid shift from the intracellular fluid. Following infusion, the extracellular fluid volume is larger, and the intracellular fluid volume and the body fluid osmolarity are unchanged. The mechanisms discussed previously for high effective circulating volume will restore normal conditions by promoting renal excretion of the volume load.

Ingestion of pure salt is an example of hyperosmotic volume expansion. Salt enters the extracellular fluid via the intestine, causing an increase in the extracellular fluid osmolarity. Water is absorbed from the intracellular fluid by osmosis. After salt absorption, the extracellular fluid volume is larger, the intracellular fluid volume is smaller, and body fluids have a higher osmolarity. Increased ADH secretion will result from high osmolarity and will initially cause further volume expansion due to water retention. The mechanisms discussed previously for high effective circulating volume will finally restore normal conditions by promoting renal Na⁺ excretion.

Patients with congestive heart failure have an expanded extracellular fluid volume, which greatly increases the likelihood of development of pulmonary edema. These patients must be cautious about the amount of salt they ingest because even small amounts can be enough to further expand their extracellular fluid volume, resulting in florid pulmonary edema.

SIADH is an example of hyposmotic volume expansion. Renal water retention delivers excess free water to the extracellular fluid, which is distributed throughout the total body water. At equilibrium, both the extracellular fluid and intracellular fluid volumes are larger, and body fluid osmolarity is reduced. The normal response (e.g., following water ingestion) would be to suppress ADH secretion. In this case, however, abnormal ADH secretion is the cause of hyposmotic volume expansion and must be addressed to restore normal effective circulating volume.

Mg²⁺ is an essential cofactor in many enzymatic reactions. Plasma [Mg²⁺] is homeostatically regulated by the balance between intestinal uptake and urinary excretion, although hormonal mechanisms are poorly defined. Only about 1% of the total Mg²⁺ in the body is in the extracellular fluid and the remainder is in the bone matrix or intracellular fluid. Dietary Mg²⁺ is reabsorbed mainly in the ileum. The normal plasma [Mg²⁺] range is from 1.3–2.1 mEq/L. Mg is present in three forms in the plasma:

1. 60% of plasma Mg²⁺ is in the free ionized form.

2. 25% of plasma Mg²⁺ is bound to plasma protein.

3. 15% of plasma Mg²⁺ is complexed to anions such as phosphate.

Mg²⁺ has an unusual profile of segmental handling along the nephron: only 25% of filtered Mg²⁺ is reabsorbed in the proximal tubule, 65% in the thick ascending limb, and 1–5% in the distal tubule. The sites of regulation of Mg²⁺ reabsorption are the thick ascending limb and the distal tubule. Loop diuretics cause urinary loss of divalent cations, including Mg²⁺ and Ca²⁺ (see Diuretics).

Urea is the end product of nitrogen metabolism; it is water soluble and has low toxicity. Plasma urea concentration (BUN) ranges from 8 mg/dL to 25 mg/dL and is not subject to homeostatic regulation. Figure 6-33 shows that FE_urea varies with a urine flow rate from about 30 to 60%. Lower rates of urea excretion are found during antidiuresis because ADH stimulates urea reabsorption in the collecting duct. ADH-dependent water reabsorption causes luminal urea concentration to increase in the collecting duct, allowing passive urea absorption via uniporters.

BUN and plasma [creatinine] levels increase in patients with renal insufficiency because reduced filtered loads decrease their urinary excretion rates. In prerenal ARF, the BUN/creatinine concentration ratio is increased (>20:1). Hypovolemia stimulates ADH secretion, and ADH specifically increases tubular urea reabsorption. Because creatinine is not reabsorbed by the tubule, more urea (than creatinine) accumulates in plasma and the BUN/creatinine concentration ratio is increased—a helpful biochemical clue in identifying patients with prerenal ARF.

Ca²⁺ homeostasis involves variable Ca²⁺ input from the gastrointestinal system and variable output by the renal system, plus exchanges of Ca²⁺ between the extracellular fluid and the bone matrix. PTH and vitamin D are the major hormones controlling Ca²⁺ balance (see Chapter 8). Calcium exists in three forms in plasma in approximately the following proportions:

1. 45% exists as free ionized Ca²⁺. The plasma concentration of free ionized Ca²⁺ is tightly regulated in the range of 1.0–1.3 mmol/L (4.0–5.2 mg/dL).

2. 45% is bound to anionic sites on plasma proteins. Protein-bound Ca²⁺ does not enter the interstitial fluid and is not filtered at the glomerulus.

3. 10% is complexed with low-molecular-weight anions such as citrate and oxalate.

Segmental Ca²⁺ Handling

The filtered load of Ca²⁺ is the product of GFR and free plasma Ca²⁺ concentration. The pattern of segmental Ca²⁺ reabsorption is similar to that of Na⁺ and results in a typical FE_Ca of 1–2%. A significant difference between Na⁺ and Ca²⁺ is the absence of Ca²⁺ reabsorption in the collecting duct. Figure 6-34 shows mechanisms of Ca²⁺ reabsorption in the thick ascending limb and the distal tubule, which are sites of regulation. In the thick ascending limb, a lumen-positive transepithelial potential difference drives paracellular Ca²⁺ reabsorption. Epithelial cells in the thick ascending limb express the extracellular Ca²⁺-sensing receptor (CaR) and are able to detect a decrease in free Ca²⁺ concentration in plasma. The response is increased Ca²⁺ uptake from the thick ascending limb due to a larger transepithelial potential difference (see Figure 6-34A). Regulation of Ca²⁺ reabsorption also occurs in the distal tubule. Ca²⁺ enters the cells of the distal tubule through Ca²⁺ channels. Ca²⁺-binding proteins called calbindins keep the cytosolic Ca²⁺ concentration low, and it must be moved across the basolateral membrane by active transport. PTH, vitamin D, and thiazide diuretics all stimulate Ca²⁺ reabsorption in the distal tubule (see Figure 6-34B).

Urinary calculi (stones) afflict many patients, causing painful renal colic. The most common chemical composition of the calculi is calcium oxalate. Hypercalciuria is the major risk factor for developing urinary calculi and is present in most patients who have calcium-based calculi. Thiazide diuretics used in the treatment of patients with hypercalciuria reduce stone formation by increasing distal tubular calcium reabsorption and therefore decreasing the urinary calcium load. This prevents supersaturation of the urine with insoluble calcium oxalate crystals and, therefore, reduces stone formation.

The concentration of inorganic phosphate in the extracellular fluid is influenced by intestinal uptake, renal excretion, and exchanges with bone. Plasma inorganic phosphate concentration is regulated in the range of 0.8 mmol/L to 1.5 mmol/L (2.5–4.5 mg/dL). Phosphate has two major forms in plasma:

1. 80% exists as alkaline phosphate (HPO₄²⁻) at a normal plasma pH of 7.4.

2. 20% exists as acid phosphate (H₂PO₄⁻).

Most phosphate is present in bone and intracellular fluid, with less than 1% in extracellular fluid. There is typically a daily dietary excess of phosphate, which is excreted from the kidney, with a fractional phosphate excretion of about 20%. Mechanisms of phosphate recovery from the filtrate are limited and restricted to Na/phosphate cotransport and are almost exclusively in the proximal tubule. Phosphate excretion is therefore highly dependent on GFR, and renal insufficiency quickly results in inadequate phosphate excretion. Increased plasma [phosphate] is a common feature of renal insufficiency. PTH is the most important physiologic regulator of plasma [phosphate]. Increased plasma [phosphate] stimulates PTH secretion directly, which increases urinary phosphate excretion by inhibiting its reabsorption in the proximal tubule.

Hyperphosphatemia is a persistent problem in patients who are in chronic renal failure due to a loss of renal excretory capacity for phosphate. Oral phosphate binders (e.g., calcium salts) are used to decrease intestinal phosphate absorption, thereby reducing plasma [phosphate].

About 98% of K⁺ in the body is in the intracellular fluid and is exchangeable with the extracellular fluid K⁺. The extracellular fluid [K⁺] is controlled within the range of 3.5 mEq/L to 5.5 mEq/L. Control of the extracellular fluid [K⁺] is essential to prevent membrane potential disruption because K⁺ conductance determines the resting membrane potential of most cells. The plasma K⁺ is affected by shifts between the intracellular fluid and extracellular fluid (internal K⁺ homeostasis) and by the balance between K⁺ ingestion and excretion (external potassium homeostasis). Aldosterone is the central hormone controlling K⁺ balance and produces effects on both internal and external homeostasis. An increase in the extracellular fluid [K⁺] stimulates aldosterone secretion directly. Cellular uptake of K⁺ in skeletal muscle is increased, which reduces extracellular fluid [K⁺], and renal K⁺ excretion is stimulated to remove excess K⁺. Disturbances in plasma [K⁺] are a common clinical problem. For example:

• Hypokalemia is defined as plasma [K⁺] < 3.5 mEq/L. The most common causes of hypokalemia are from gastrointestinal losses (e.g., diarrhea, vomiting, or gastric suctioning) or from a renal loss (e.g., caused by the use of a diuretic).

• Hyperkalemia is defined as plasma [K⁺] > 5.5 mEq/L.

In patients with chronic renal failure, hyperkalemia is an indication for hemodialysis treatment. Acute hyperkalemia can be rapidly fatal as a result of cardiac arrhythmia. Medical treatment of hyperkalemia includes four approaches:

1. Calcium gluconate infusion. Increased plasma Ca²⁺ stabilizes cardiac membrane potential, decreasing the immediate risk of arrhythmia.

2. Insulin and glucose infusion. Insulin infusion drives K⁺ back into the intracellular fluid, decreasing plasma levels; concomitant glucose infusion allows for continuous insulin administration without inducing hypoglycemia.

3. Oral sodium polystyrene sulfonate (Kayexalate). This intestinal K⁺ chelator reduces K⁺ absorption and increases fecal K⁺ elimination.

4. β₂ agonists (such as albuterol or epinephrine). These drugs provide a short-acting mechanism to temporarily drive K⁺ into the intracellular fluid.

Internal K⁺ Homeostasis

Figure 6-35 summarizes factors other than aldosterone that influence K⁺ distribution between the extracellular fluid and the intracellular fluid.

• Insulin stimulates K⁺ movement from the extracellular fluid to the intracellular fluid. A single meal can contain as much K⁺ as the entire extracellular fluid, so rapid sequestration of ingested K⁺ into intracellular fluid is needed to prevent hyperkalemia after eating. Insulin causes K⁺ uptake by the liver and skeletal muscle in addition to its effects on glucose homeostasis (see Chapter 8). Insulin infusions can be used to control hyperkalemia.

• Epinephrine stimulates K⁺ movement from the extracellular fluid to the intracellular fluid. An acute K⁺ load is delivered into the extracellular fluid by exercising muscle. Secretion of epinephrine during exercise stimulates K⁺ reuptake into skeletal muscle cells through the activation of the β₂ receptors.

• Disturbances in acid-base balance also affect internal K⁺ distribution. In acidosis, some H⁺ is buffered by the intracellular fluid and is associated with K⁺ efflux from the cells, thereby increasing plasma K⁺. In alkalosis, H⁺ exits the cells in exchange for K⁺, thereby reducing plasma K⁺.

Renal K⁺ Handling

Urinary K⁺ excretion varies with dietary K⁺ intake. To achieve excretion of the moderate K⁺ excess found in a normal diet, the fractional K⁺ excretion (FE_K) is typically 10–20%. FE_K can be 0% in states of K⁺ deficiency, or it can reach 150–200% in states of K⁺ excess. Figure 6-36A summarizes segmental K⁺ handling (external K⁺ homeostasis). Seventy percent of filtered K⁺ is reabsorbed in the proximal tubule, and an additional 25% is reabsorbed in the thick ascending limb. K⁺ reabsorption at these proximal sites does not respond to changes in K⁺ balance and are not physiologically regulated.

Secretion of K⁺ from the principal cells in the late distal tubule and the cortical collecting duct is the most important determinant of urinary K⁺ output. The mechanism of K⁺ secretion by the principal cells is shown in Figure 6-36B. High intracellular K⁺ activity is generated by the Na⁺/K⁺-ATPase in the basolateral membrane; K⁺ secretion occurs through K⁺ channels in the luminal cell membrane. Aldosterone simultaneously stimulates the principal cells to secrete K⁺ while promoting Na⁺ uptake. Aldosterone stimulates Na⁺ influx via the Na⁺ channels, causing depolarization of the luminal cell membrane and thereby increasing the driving force for K⁺ secretion. Net reabsorption of K⁺ is also possible in the collecting duct in states of K⁺ depletion; α-intercalated cells reabsorb K⁺ in exchange for H⁺, via the H/K-ATPase.

An increase in Na⁺ delivery to the cortical collecting duct causes an increase in K⁺ secretion by the principal cells. For example, thiazide and loop diuretics inhibit Na⁺ reabsorption upstream from the cortical collecting duct, causing high Na⁺ delivery to the cortical collecting duct, which drives further K⁺ secretion by the principal cells.

The presence of luminal fixed anions, normally not present in the cortical collecting duct, also stimulates K⁺ secretion; for example, the large HCO₃⁻ load present in the tubule in metabolic alkalosis.

Normal plasma pH is maintained within the range of 7.35 to 7.45. Regulation of pH occurs by varying CO₂ excretion from the lungs and by varying the rate of H⁺ excretion and HCO₃⁻ production in the kidney. In most clinical acid-base problems, the primary variables considered are pH, arterial Pco₂, and [HCO₃⁻]; the normal values are 7.40, 40 mm Hg, and 24 mmol/L, respectively.

Acids and Bases

Acids are molecules that release H⁺ in solution; bases are ions or molecules that can accept H⁺. Strong acids rapidly dissociate releasing large amounts of H⁺; weak acids partially dissociate releasing less H⁺. Strong bases react rapidly and strongly to neutralize H⁺; weak bases bind less H⁺. Most acids and bases encountered physiologically are “weak.” The [H⁺] in extracellular fluid is only 0.00004 mmol/L = 40 nmol/L. The logarithmic pH scale is used to express these very small values:

A 10-fold H⁺ concentration change represents a 1 unit pH change; a twofold H⁺ concentration change represents approximately a 0.3 unit pH change. The limits of extracellular fluid pH compatible with life are about 6.8 to 7.8.

Daily metabolism produces about 15,000 mmol of CO₂ (volatile acid). Metabolism produces an additional 70 mmol of fixed acids (also called metabolic or nonvolatile acid), including organic acids and phosphoric and sulfuric acids. Defense against pH disturbance has three components:

1. Buffers provide limited but immediate limitations on pH change.

2. Changes in ventilation and CO₂ excretion can occur over seconds to minutes to provide a rapid second line of defense against pH change.

3. Renal system H⁺ excretion and HCO₃⁻ synthesis is the final line of defense, acting over a period of hours to days to prevent sustained pH change.

Buffers

A buffer is a substance that can reversibly bind H⁺. Buffering power expresses the effectiveness of a buffer system and is defined as “moles of strong acid added to 1 L of solution to reduce pH by 1 unit” or “moles of strong base added to 1 L of solution to increase pH by 1 unit.” The most important buffer in the extracellular fluid is the bicarbonate buffer system, created by the reaction between water and CO₂ to form carbonic acid, which dissociates to H⁺ and HCO₃⁻. The pH resulting from this reaction is calculated from the Henderson-Hasselbalch equation:

Example

A healthy person in acid-base homeostasis has a plasma [HCO₃⁻] of 24 mmol/L, an arterial Pco₂ of 40 mm Hg, and a plasma pH of 7.4. Equation 6-9 correctly predicts this normal plasma pH:

The Henderson-Hasselbalch equation predicts that plasma pH is a simple function of the ratio of HCO₃⁻ to Paco₂. If the pH increases, it could be due to an increase in HCO₃⁻ (metabolic alkalosis) or a decrease in arterial Pco₂ (respiratory alkalosis). If the pH decreases, it could be due to a decrease in HCO₃⁻ (metabolic acidosis) or an increase in arterial Pco₂ (respiratory acidosis).

Respiratory Contribution to Acid-base Balance

Normal pulmonary function balances CO₂ excretion with metabolic CO₂ production. Arterial Pco₂ is monitored primarily by central chemoreceptors (see Chapter 5); alveolar ventilation increases to excrete more CO₂ when the arterial Pco₂ increases and decreases when the arterial Pco₂ decreases. Pulmonary pathology may result in defects in respiratory performance or control that cause acid-base disturbances. Hypoventilation results in high arterial Pco₂ (respiratory acidosis); hyperventilation results in low arterial Pco₂ (respiratory alkalosis).

Changes in CO₂ excretion can help to compensate for metabolic acid-base disturbances. Figure 6-37 shows that low plasma pH is a potent stimulus to increase alveolar ventilation, a response that is mediated through peripheral chemoreceptors (see Chapter 5). The resulting decrease in arterial Pco₂ increases the plasma pH back toward normal. An increase in plasma pH causes a smaller change in alveolar ventilation than an equivalent decrease in plasma pH. This is necessary because correction for increased pH would require low ventilation rates, which compromise oxygenation of the blood.

Renal Regulation of Acid-base Balance

The kidney has two major functions related to acid-base homeostasis:

1. Regulation of plasma [HCO₃⁻] in the range of 22 mmol/L to 28 mmol/L. The kidney can excrete HCO₃⁻, and it can generate new HCO₃⁻. Under most circumstances, the renal venous blood contains more HCO₃⁻ than the renal arterial blood, reflecting continuous renal HCO₃⁻ production. The kidney generates just enough HCO₃⁻ to neutralize net acid production from metabolism.

2. Excretion of fixed metabolic acids. Acid in the urine is mainly in the form of ammonium ions (NH₄⁺) and phosphoric acid (H₂PO₄⁻).

Recovery of filtered HCO₃⁻ and net acid excretion is usually required to maintain acid-base balance—almost all the filtered HCO₃⁻ must be recovered. Most HCO₃⁻ reabsorption occurs in the early proximal tubule via the mechanism shown in Figure 6-38. H⁺ is secreted into the lumen via the Na/H exchange, where it combines with filtered HCO₃⁻ to form carbonic acid. The enzyme carbonic anhydrase is anchored to the brush-border membrane of the proximal tubular cells, where it generates CO₂ from carbonic acid. CO₂ diffuses into the proximal tubule cells, where cytoplasmic carbonic anhydrase facilitates carbonic acid formation again. H⁺ and HCO₃⁻ are produced inside the cell from dissociation of carbonic acid. H⁺ is recycled for secretion into the lumen, and HCO₃⁻ enters extracellular fluid via a Na/HCO₃⁻ cotransporter in the basolateral membrane.

Bicarbonaturia (increased urinary HCO₃⁻ loss) is caused by carbonic anhydrase inhibitors such as acetazolamide, which disrupt tubular HCO₃⁻ reabsorption. Renal tubular acidosis type 2 (or proximal renal tubular acidosis) is a condition in which HCO₃⁻ resorption in the proximal tubules is impaired, resulting in urinary HCO₃⁻ loss in the setting of systemic acidosis.

Renal ammonia production accounts for approximately 75% of H⁺ excretion and occurs in the form of ammonium ions (NH₄⁺). The proximal and distal tubules produce ammonia (NH₃) from glutamate in the mitochondria. NH₃ consumes free H⁺ and is converted to NH₄⁺. Figure 6-39A shows that NH₄⁺ is secreted as an alternate substrate to H⁺ via the Na/H exchangers in the luminal membrane. Deamination of glutamate also produces 2HCO₃⁻, which are transported into the extracellular fluid across the basolateral membrane. The net effect of this process is excretion of acid in urine, plus generation of new HCO₃⁻ to replenish that consumed by buffering of metabolic acids in the extracellular fluid.

Titratable acid excretion is approximately 25% of H⁺ excretion and is in the form of phosphate ions. When H⁺ is secreted into the tubule lumen, it may be buffered by HPO₄^2- to produce H₂PO₄⁻. Figure 6-39B shows that H⁺ secreted by the proximal tubule is derived from carbonic acid; HCO₃⁻ is generated concurrently and enters the extracellular fluid by cotransport with Na⁺ across the basolateral membrane. The net effect of this process is urinary excretion of acid, plus generation of new HCO₃⁻ for the extracellular fluid. Acid-excreted phosphate ions are measured as “titratable acids,” because titration of urine to the plasma pH of 7.4 does not include H⁺ associated with NH₄⁺.

Acidification of urine occurs along the entire renal tubule. The proximal tubule secretes the most H⁺, but the proximal tubular fluid pH usually does not decrease below 6.8 due to the large amount of HCO₃⁻ and phosphate buffers present in the glomerular filtrate. The cells in the loop of Henle and the distal tubule and the principal cells in the cortical collecting duct all secrete H⁺ via the Na/H exchange. The α-intercalated cells in the collecting duct use primary active H⁺ secretion via the H⁺-ATPase and H/K-ATPase.

Na/H exchange in the distal tubule and the principal cells of the cortical collecting duct is stimulated by aldosterone. Hyperaldosteronism can be associated with metabolic alkalosis as a result of excessive H⁺ secretion into the urine.

H⁺/K⁺ Interactions

In many situations, there is a reciprocal relationship between the secretion of H⁺ and K⁺ in the collecting duct. This contributes to a general relationship in which acidosis is associated with hyperkalemia and alkalosis is associated with hypokalemia. For example, if the collecting duct is secreting a large amount of H⁺ to combat a primary acidosis, then less K⁺ is excreted and hyperkalemia may develop. Renal defense against alkalosis includes reducing H⁺ secretion, which increases K⁺ excretion and may cause hypokalemia. There are exceptions to this general relationship; for example, increasing Na⁺ delivery to the collecting duct during treatment with loop or thiazide diuretics drives more secretion of both H⁺ and K⁺ and can result in both alkalosis and hypokalemia.

Acid-base Disorders

Figure 6-40 is an algorithm that is used to describe acid-base disturbances. Respiratory disorders are defined based on arterial Pco­₂:

• Paco₂ > 45 mm Hg defines respiratory acidosis.

• Paco₂ < 35 mm Hg defines respiratory alkalosis.

Metabolic disorders can be defined based on plasma HCO₃⁻ concentration:

• HCO₃^– < 22 mEq/L defines metabolic acidosis.

• HCO₃^– > 28 mEq/L defines metabolic alkalosis.

Base excess is another way of defining metabolic acid-base disturbances. Base excess is a calculated value that estimates the size of a metabolic disturbance independent of Pco_2. It is defined as the amount of strong acid (or base), in mmol/L, needed to titrate the pH of 100% oxygenated blood to 7.4 at 37°C and at a Pco₂ of 40 mm Hg:

• Base excess > 2 mmol/L defines metabolic alkalosis.

• A negative base excess (a base deficit) > 2 mmol/L defines metabolic acidosis.

The most common clinical presentation is two opposing acid-base disorders in which a primary disorder is compensated by a secondary disorder. Compensation refers to responses that normalize plasma pH. Table 6-4 summarizes the four primary acid-base disorders and the expected pattern of physiologic compensation.

Metabolic acidosis can be caused by excess production or ingestion of fixed acids. Common examples include accumulation of ketoacids in diabetic patients or accumulation of lactic acid during hypoxia. Another common example is failure of the kidney to excrete metabolic acid in patients with chronic renal failure. Ingestion of poisons such as methanol and ethylene glycol or excessive ingestion of aspirin also results in the generation of excess fixed acids. Excess H⁺ is buffered by plasma HCO₃⁻, causing a decrease in plasma [HCO₃⁻], which defines metabolic acidosis. Elevated plasma H⁺ stimulates ventilation via peripheral chemoreceptors. Compensatory respiratory alkalosis is usually present, which reduces the arterial Pco₂ and increases the pH toward normal. The resolution of metabolic acidosis without treatment requires increased renal generation of new HCO₃⁻ and increased H⁺ excretion via NH₃ production and titratable acid excretion.

Metabolic acidosis can also be caused by the loss of HCO₃⁻. The most common example is gastrointestinal fluid loss due to diarrhea; however, renal HCO₃⁻ losses are also possible and may occur, for example, in patients with renal tubular acidosis. Calculation of the serum anion gap is used to help differentiate between metabolic acidosis caused by the addition of acid or the loss of HCO₃⁻. Anion gap is calculated by subtracting the sum of serum Cl⁻ and HCO₃⁻ concentrations from serum Na⁺ concentration:

Extracellular fluid is an electroneutral solution in which the total number of anions and cations must be equal. Anion gap is normally in the range of 8–16 mEq/L, and indicates the concentration of unmeasured anions such as protein, phosphate, sulfate, and citrate. The addition of a metabolic acid consumes HCO₃⁻ and replaces it with a conjugate base anion (e.g., lactate ions in the case of lactic acid). This adds to the unmeasured anions, which increases the calculated anion gap. When metabolic acidosis is caused by a loss of HCO₃⁻, there is an increase in Cl⁻ ( hyperchloremic metabolic acidosis) rather than the addition of other unmeasured anions, and the anion gap is normal.

Calculating the anion gap is helpful in approaching the differential diagnosis of metabolic acidosis.

1. The most common causes of metabolic acidosis with an increased anion gap are listed below. (Note: MULEPAK can be a helpful mnemonic for remembering the causes of an anion gap metabolic acidosis.)

   • Methanol ingestion

   • Uremia

   • Lactic acidosis

   • Ethylene glycol ingestion

   • Paraldehyde ingestion

   • Aspirin overdose

   • Ketoacidosis

2. The most common causes of metabolic acidosis without an increased anion gap are:

   • Diarrhea

   • Carbonic anhydrase inhibitors

   • Renal tubular acidosis

   • Hyperalimentation (intravenous feeding)

Example

A 16-year-old girl with diabetes mellitus was found unconscious and unresponsive. The results of arterial blood gas analysis showed the following abnormalities:

• Po₂ = 90 mm Hg

• Pco₂ = 36 mm Hg

• [HCO₃⁻] = 7 mEq/L (normal = 22–28 mEq/L)

• pH = 6.91 (normal = 7.35–7.45)

• Plasma [Na⁺] = 145 mEq/L

• Plasma [Cl⁻] = 110 mEq/L

The acid-base disorder described in the algorithm in Figure 6-40 is metabolic acidosis (low [HCO₃⁻]) with no respiratory component (normal arterial Pco₂), which is producing a severe acidemia (low plasma pH). The anion gap is calculated as follows:

Comment

The patient has diabetic ketoacidosis, which produces an increased anion gap. A metabolic acidosis is present with no respiratory compensation, resulting in a severe life-threatening acidemia.

Metabolic alkalosis most commonly results from a loss of gastric H⁺ due to vomiting, and results in excess HCO₃⁻ in the blood. A net gain of HCO₃⁻ by the renal system can also occur; an example is “contraction alkalosis”, when HCO₃⁻ retention occurs as a side-effect of responses to low effective circulating volume. HCO₃⁻ retention occurs with low effective circulating volume by a combination of a low GFR, which reduces filtered HCO₃⁻ load, and avid proximal tubular reabsorption. Aldosterone levels are also increased when the effective circulating volume is low, causing increased H⁺ secretion by the distal nephron. Other causes of hyperaldosteronism may also cause metabolic alkalosis, including Cushing's disease (see Chapter 8).

Increased arterial blood pH (alkalemia) usually results in a degree of compensatory respiratory acidosis. Arterial Pco₂ increases as a result of reduced alveolar ventilation and decreases the pH toward normal. Physiologic correction of metabolic alkalosis requires increased renal excretion of HCO₃⁻, with reduced rates of acid excretion and HCO₃⁻ retention.

Metabolic alkalosis may be either chloride sensitive or chloride resistant. The presence of high plasma [HCO₃⁻] in metabolic alkalosis “displaces” Cl⁻ from the plasma. Patients with metabolic alkalosis are given intravenous saline solution (NaCl); if Cl⁻ is retained in the plasma, the [HCO₃⁻] is reduced and the metabolic alkalosis is Cl⁻ sensitive. Examples of Cl⁻-sensitive metabolic alkalosis include contraction alkalosis and vomiting or gastric suction. Cl⁻-resistant metabolic alkalosis occurs if urinary Cl⁻ excretion is persistently large; this occurs, for example, during active use of loop or thiazide diuretics or in tubular NaCl reabsorption disorders such as Bartter's or Gitelman's syndromes.

Example

 A 2-year-old child who is lethargic and dehydrated has a 3-day history of vomiting. The results of arterial blood gas analysis show the following abnormalities:

• Po₂ = 90 mm Hg

• Pco₂ = 44 mm Hg

• [HCO₃⁻] = 37 mEq/L (normal = 22–28 mEq/L)

• pH = 7.56 (normal = 7.35–7.45)

The acid-base disorder described in the algorithm in Figure 6-40 is metabolic alkalosis (high [HCO₃⁻]) with no respiratory component (normal arterial Pco₂), which is producing an alkalemia (high plasma pH). Treatment of the patient with saline infusion and an antiemetic agent will restore acid-base homeostasis.

Comment

Metabolic alkalosis in this child was caused by a loss of HCl in gastric fluids. The alkalosis was Cl⁻ sensitive because fluid loss was stopped and the renal system was able to retain Cl⁻ and excrete HCO₃⁻.

Respiratory acidosis is caused by inadequate alveolar ventilation that results in CO₂ retention. Inadequate ventilation may result from neuromuscular disorders, airway obstruction, or ingestion of agents that suppress breathing (e.g., narcotics). An increase in arterial Pco₂ defines respiratory acidosis, which increases plasma [HCO₃⁻] and [H⁺] through the Henderson-Hasselbalch equilibrium reaction. If respiratory acidosis occurs acutely, there is inadequate time for renal compensation. In chronic respiratory acidosis, the renal system normalizes the pH by excreting more acid and producing more HCO₃⁻, which is added to extracellular fluid.

Example

A 24-year-old man who is a known heroin addict was found unresponsive with a hypodermic needle in his arm. The results of arterial blood gas analysis showed the following abnormalities:

• Po₂ = 50 mm Hg (normal = 80–100 mm Hg)

• Pco₂ = 80 mm Hg

• [HCO₃⁻] = 23 mEq/L (normal = 22–28 mEq/L)

• pH = 7.08 (normal = 7.35–7.45)

The acid-base disorder described in the algorithm in Figure 6-40 is respiratory acidosis (high arterial Pco₂) with no metabolic component (normal [HCO₃⁻]), which is producing a severe acidemia (low plasma pH).

Comment

The patient overdosed on a narcotic that caused respiratory depression, alveolar hypoventilation, and respiratory acidosis.

Respiratory alkalosis is caused by excessive alveolar ventilation, resulting in greater CO₂ loss than production. Increased ventilation is most commonly a response to hypoxemia (e.g., ascent to high altitude; pulmonary embolism); another common cause is psychogenic hyperventilation. A low arterial Pco₂ decreases the plasma [HCO₃⁻] and [H⁺]. If respiratory alkalosis occurs acutely, there is no time for renal compensation. In chronic respiratory alkalosis, the renal system normalizes the pH by excreting less acid and producing less “new” bicarbonate.

Example

A 56-year-old man suffered a panic attack while awaiting surgery. The results of arterial blood gas analysis showed the following abnormalities:

• Po₂ = 112 mm Hg (normal 80–100 mm Hg)

• Pco₂ = 24 mm Hg

• [HCO₃⁻] = 23 mEq/L (normal = 22–28 mEq/L)

• pH = 7.60 (normal = 7.35–7.45)

The acid-base disorder described in the algorithm in Figure 6-40 is respiratory alkalosis (low arterial Pco₂) with no metabolic component (normal plasma [HCO₃⁻]), which is producing an alkalemia (high plasma pH).

Comment

The patient's panic attack resulted in acute hyperventilation and respiratory alkalosis. The acid-base abnormality will be readily corrected when breathing returns to normal.

Compensation of Primary Acid-Base Disorders

Compensation refers to responses that normalize plasma pH. Figure 6-41 illustrates compensatory responses and includes the expected size of changes in [HCO₃⁻] or arterial Pco₂. Compensation usually is not complete, which allows the primary acid-base disorder to be recognized as the disorder that is consistent with plasma pH. For example, if both alkalosis and acidosis are present and the pH is acidic, the acidosis must be considered the primary disorder, partially compensated by the alkalosis.

Figure 6-41 also indicates expected changes in the arterial Pco₂ and [HCO₃⁻] during acute and chronic compensation. When [H⁺], [HCO₃⁻], and arterial Pco₂ differ from the expected compensatory range, the patient has a complex acid-base disorder. This can arise if more than one acid-base disturbance is present with independent causes such as a trauma patient in shock, and respiratory failure can then result in primary lactic acidosis and a primary respiratory acidosis, or it can occur from prior clinical interventions such as intravenous infusion with fluids containing buffers.

Excessive aspirin ingestion causes a mixed acid-base disorder. Aspirin uncouples oxidative phosphorylation, resulting in a primary metabolic lactic acidosis. Additionally, the direct effects of aspirin on the respiratory centers in the medulla cause the central chemoreceptors to be more sensitive to arterial Pco₂ levels, which results in a primary respiratory alkalosis.

Example

A 42-year-old man in chronic renal failure is being treated with hemodialysis. The results of arterial blood gas analysis showed the following abnormalities:

• Po₂ = 87 mm Hg

• Pco₂ = 28 mm Hg (normal = 35–45 mmHg)

• [HCO₃⁻] = 15 mEq/L (normal = 22–28 mEq/L)

• pH = 7.35

• Anion gap = 20 mEq/L

The acid-base disorder described in the algorithm in Figure 6-40 is metabolic acidosis (low [HCO₃⁻]) with a respiratory alkalosis (decreased arterial Pco₂) and a normal pH.

Comment

The primary acid-base disorder is a chronic metabolic acidosis produced by renal failure and loss of urinary H⁺ excretion. The expected respiratory compensation, as described in Figure 6-41, is approximately a 1.3-mm Hg decrease in arterial Pco₂ for every 1 mEq/L decrease in [HCO₃⁻]. In this case, [HCO₃⁻] is 24–15 = 9 mEq/L below normal. The expected decrease in arterial Pco₂ is 9 × 1.3 = 11.7, which corresponds with the observed data (28 mm Hg is 12 mm Hg less than a normal average arterial Pco₂ of 40). The respiratory compensation is complete because pH is in the normal range. Note: this is not a primary chronic respiratory alkalosis compensated by metabolic acidosis because the plasma pH is 7.35 and compensation never overshoots the normal pH of 7.40. The same conclusion is indicated by the observation that the decrease in plasma [HCO₃⁻] in this patient differs significantly from that expected for compensation of a chronic respiratory alkalosis. An arterial Pco₂ of 28 mm Hg is 40–28 = 12 mm Hg less than normal, giving an expected decrease in [HCO₃⁻] of only 4–5 mEq/L (Figure 6-41), whereas the actual decrease in [HCO₃⁻] is 9 mEq/L.