Physiology - An Illustrated Review

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TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

1

Water deficit, salt excess

Water excess, salt deficit

2

Hypertonic environment

Hypotonic environment

FPO

H2O

H2O

= solute particles

Cell shrinks

Cell swells

Renal Physiology

Unit TOC to come

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), Š 2010 Thieme Medical Publishers, Inc.

Renal Physiology I Features and Functions

A. Features and Functions A.1 Fluid Compartments The role of the kidneys is to maintain a balance between water content and concentration of solutes in the body through urine production. The water content and specific solutes are divided into intra- and extracellular fluids.

Types of Body Fluid Water ​is the major component of body fluid compartments. It accounts for about 60% of body weight and is referred to as total body water (TBW). The percentage of body weight made up of TBW varies with gender and age (Fig A.1). Women tend to have a lower percentage of TBW. This percentage declines with increased age and increased amounts of body fat.

Intracellular fluid (ICF) ​is ~40% of body weight. It is the fluid within the body’s cells (cytoplasm)

(Fig A.2).

Fig A.1 ▶ Total body water (TBW) content.

Fraction of TBW to body weight

1.00

0.75 0.64

Men Infant

0.53

0.53

Women

Men

Young

0.46

Women Old

Fig A.2 ▶ Fluid compartments of the body. ECF, extracellular fluid; ICF, intracellular fluid.

Fraction of body weight

~0.19

ICF

~0.35

Interstitial H2O

Cellular H2O (ICF)

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Indicator

Antipyrine

Plasma H2O

Inulin

Transcellular H2O Evans blue

ECF

0.015 0.045

Total body H2O = 0.6

A-2

Features and Functions I Renal Physiology

Extracellular fluid (ECF) ​is ~20% of body weight. It is made up of the following components: 1. Plasma volume (~4%) 2. Interstitial fluid volume (~15%)

– Includes lymph

3. Transcellular fluid volume (~1–3%)

– Includes cerebrospinal fluid, peritoneal fluid, synovial fluids, and secretions

The kidneys directly regulate the concentration of water and solutes in the ECF, keeping the overall concentrations throughout the body at a healthy level. This is called the range of normal value for any substance.

Measuring the Sizes of Body Fluid Compartments The volumes of fluid compartments can be measured indirectly by indicator dilution methods.

General equation ​The volume of a compartment is found by determining the final concentration of a known quantity of a marker substance that has been added to the compartment using the equation V = Q/C, where – V is the volume at which the substance X is uniformly distributed – C is the measured final concentration of X. – Q is the quantity of X added to the compartment, minus the amount lost from the compartment by excretion or metabolism during the measurement.

Estimation Procedures The volume of different components of body water cannot be measured directly, so substances are added to specific components, and their dilution provides an estimate of the volume.

Total body water ​can be measured using 1. Antipyrine 2. Tritiated water (THO) 3. Deuterium oxide (D2O) Extracellular fluid ​volume is measured using substances that will not enter cells: 1. Saccharides (e.g., inulin, sucrose, or mannitol) 2. Ions (e.g., thiosulfate, thiocyanate, or radioactive chloride) Interstitial fluid ​volume is not measured directly but is calculated as the difference between ECF and plasma volume.

Plasma volume i​ s determined using substances that neither leave the vasculature nor enter red blood cells.

1. Evans blue dye 2. Radioactive serum albumin Another method is to label red blood cells with 32P or 51Cr and reinject them into the circulation. The dilution of tagged red blood cells and the hematocrit are used to determine red blood cell volume and plasma volume.

Intracellular fluid ​volume is calculated as the difference between TBW and ECF volume.

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

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A-4

Renal Physiology I Features and Functions

Solutes in Body Fluids Normally functioning kidneys regulate the concentrations of solutes to keep them at a healthy level despite fluctuations in intake and metabolism.

Electrolytes ​account for up to 95% of the total solutes. They are the most abundant constituents of body fluids next to water. Organic solutes (glucose, amino acids, urea, etc.) constitute only a small portion of total solutes. Electrolytes

1. Contribute to osmotic pressure 2. Function as substrates for membrane transport 3. Determine membrane potential and pH of body fluids Intracellular solutes ​ 1. K+ and Mg2+ are the major cations 2. Proteins and phosphates are the major anions Osmolality Osmolality is the concentration of osmotically active solute particles in any compartment. The osmolality of the ICF and ECF compartments are normally the same. Average value for osmolality = 290 mOsm/kg of body water (range 275–304 mOsm/kg).

The common rounded value is 300 mOsm/kg. Osmolality is regulated in any one person within a few mOsm/kg. In ICF, K+, charged proteins, and associated ions contribute to osmolality, whereas in ECF, NaCl content is key.

Extracellular solutes ​ 1. Na+, Cl–, and HCO3– are the major ions 2. Proteins

– Interstitial fluid is relatively free of proteins.

– Plasma has important proteins.

A.2. Functions of the Kidneys The role of the kidneys is to maintain the volume and composition of the extracellular fluid (ECF). They do this by regulating urine content through filtration, reabsorption, and secretion. Urine is more or less concentrated and has more or less total volume depending on the need to rid the body of water, ions, or both. The concentrations of the following four factors are regulated through the kidneys’ production of urine.

1.

2.

3.

4.

Renal Shutdown Acute renal failure produces coma and death in a few days, due to acidosis, hyperkalemia (high plasma potassium), and hyponatremia (low plasma sodium). Urea and creatinine levels are also elevated.

Conservation of Volume

Water Electrolytes, such as Na+, K+, PO42–, and Cl– Acid or base (pH) content (H+)

Nitrogenous by-products (from metabolism of proteins, mainly urea)

In addition to these functions, the kidneys release hormones such as renin and erythropoietin.

Water balance. ​The water intake (liquids consumed and metabolically produced) normally equals

water output (evaporation from the skin and lungs plus losses via urine, sweat, and feces) (Fig A.3).

Volume of water intake is – Influenced by sociological and habitual factors – Controlled primarily by thirst mechanisms in the hypothalamus Final control of body water is precisely regulated by water loss in the kidneys.

The total amount of substances taken in and produced by the body equals the total amount consumed and excreted. All substances in the body fluids come from either intake or metabolism. All substances are eliminated by either excretion or metabolic consumption.

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Features and Functions I Renal Physiology

A-5

Fig A.3 ▶ Water balance.

Deficit

Intake: ~2.5 L/day

Increased thirst

Supplied by: water of oxidation

0.3 L

food 0.9 L

beverages

1.3 L

Excreted: in feces by respiration and perspiration as urine

Water balance

0.1 L 0.9 L 1.5 L

Output: ~2.5 L/day Increased urine output

Excess

Electrolytes ​are affected only by ingestion and excretion. Sodium and potassium are the most important electrolytes for osmotic balance in the body. Electrolyte output is tightly regulated via urinary excretion.

pH regulation ​The kidneys regulate acid–base balance by reabsorbing or producing bicarbonate and by excreting excess acid (H+).

Elimination of by-products ​The kidneys also rid the body of many waste substances and foreign chemicals, such as drugs and pesticides.

Hormones Produced by the Kidneys Renin ​helps to regulate total body Na+, ECF volume, and blood pressure.

Elimination of Substances Besides the kidneys, the liver breaks down drugs and other substances, but ultimately those simpler compounds are excreted by the kidneys (or in the feces).

Vasoactive substances ​(prostaglandins and kinins) are autocoids, which act on – Renal hemodynamics – Na+ and water excretion – Renin release

Hormones regulating vitamin D3 ​stimulate calcium absorption from gut, bone, and renal tubular

fluid. The liver converts vitamin D3 to the 25-hydroxy form, which the kidneys convert to the most active vitamin D form, cholecalciferol.

Erythropoietin ​stimulates red blood cell formation.

Erythropoietin Patients on renal dialysis often require injections of erythropoietin. It helps to stimulate their production of red blood cells and avoid anemia. Their kidneys are not functioning, so they do not produce erythropoietin.

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

A-6

Renal Physiology I Features and Functions

A.3 Renal Anatomy and Processes The kidney has an outermost cortical layer and a central medullary layer (Fig A.4). The functional unit of the kidney is the nephron. Each nephron is a tube that starts and ends in the cortex and has a short or long loop into the medulla (Fig. A.5).

Fig A.4 ▶ Anatomy of the kidney.

Cortical nephron

2

Afferent arteriole

3

Peritubular capillary network

Cortex

Juxtamedullary nephron

1

8 1

Interlobular artery Glomerulus

7 Proximal tubule

4

Outer stripe

Outer medulla

4

Inner stripe

6

Arcuate artery

Distal tubule Loop of Henle

Vasa recta

9

Inner medulla

5 Collecting duct

Renal artery Renal vein Ureter

Kidney

Papilla

1-arcuate arteries 2-interlobular arteries 3- proximal convoluted tubule 4-proximal straight tubule 5-thin descending limb 6-thick ascending limb 7-distal convoluted tubule 8-connecting tubule 9-collecting duct

Fig A.5 ▶ Glomerulus and Bowman capsule. Capillaries in the vascular glomerulus have intimate contact with the membranes of Bowman capsule, the beginning of the nephron. Each nephron has two arterioles and two sets of capillaries associated with it.

Afferent arteriole

Urine side

Efferent arteriole

Slit membrane Pores 5 nm

Fenestrae 50 –100 nm

Blood side

Capsular space Glomerular capillaries

Bowman capsule Glomerulus Origin of proximal tubule

Podocyte

Pedicel

Endothelium Basement membrane

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Features and Functions I Renal Physiology

A-7

Sequence of blood flow through the kidneys ​ 1.

2.

3.

4.

5.

Arterial blood is delivered to glomerular capillaries via afferent arterioles.

Plasma passes through glomerular membrane pores.

Plasma filtrate passes into the Bowman capsule.

Blood that is not filtered leaves the glomerulus via efferent arterioles.

Blood flows into peritubular capillaries surrounding the nephrons.

Processes taking place in the nephron ​ 1. Ultrafiltration: as blood passes through the kidneys, substances are removed. [XREF] 2. Tubular reabsorption: substances that the body needs are returned to the blood. [XREF] 3. Tubular secretion: substances are added to the filtrate and excreted. [XREF] Renal energy sources. ​Different parts of the kidney have different energy sources. The renal cortex makes use of aerobic oxidative metabolism (mostly of fatty acids). Renal medullary structures metabolize glucose anaerobically.

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Glomerular Filtration Glomerular filtration is indiscriminate, as everything in plasma is filtered except large proteins. Glomerular capillaries and basement membranes are freely permeable only to small solutes. Glomerular filtrate contains the same concentrations of small molecules as the plasma. Normally, the filtrate will be almost free of larger molecules, namely proteins.

B-8

Renal Physiology I Glomerular Filtration

B. Glomerular Filtration B.1 Key Renal Rates The following renal rates characterize glomerular filtration.

Glomerular filtration rate (GFR) ​is the volume of plasma filtered per minute by all glomeruli in the kidneys. The magnitude of the GFR is an index of kidney function.

– The average GFR for a healthy 70 kg (154 lb) man is 125 mL/min.

– GFR is lower in children and women and higher in larger people.

Renal plasma flow (RPF) ​is the volume of plasma entering the kidneys per minute.

– Average RPF is ~600 mL/min.

– About 20% of this RPF is filtered at the glomerulus, so the GFR is about 120 mL/min.

Filtration fraction ​is the fraction (one fifth) of total plasma volume that is filtered. If filtration fraction increases, then GFR increases. The filtration fraction increases when the resistance to blood flow in efferent arterioles increases.

Renal blood flow (RBF) ​is the amount of blood supplied to the kidneys.

– This constitutes ~1 L/min, or 20% of cardiac output.

RBF is a little less than double the RPF, as plasma represents about 55 to 60% of whole blood. Changes in renal blood flow affect total body blood pressure. Blood pressure increases when RBF decreases.

B.2 Factors Affecting Glomerular Filtration Three factors determine the glomerular filtration rate (GFR).

1. Filtration forces 2. Permselectivity of glomerular membranes 3. Rate of renal plasma flow (RPF)

Filtration Forces Ultrafiltration of plasma occurs as plasma moves from glomerular capillaries into the Bowman capsule under the influence of net filtration pressures (Fig B.1). Glomerular filtration is the same mechanism as systemic capillary filtration. The balance between hydrostatic and oncotic forces across the glomerular membrane determines the direction of fluid movement (just like for systemic capillaries).

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Glomerular Filtration I Renal Physiology

B-9

Fig B.1 ▶ Filtration.

6P

Pa

a

Example

Pb

Glomerular capillary

Pa > Pb and 6P > 6/x

x

b

Blood Water filtration from a to b

6/x

Water flux JV = Kf · (6P – 6/x)

Primary urine

6P

Filtrate

6/

(= oncotic pressure of plasma proteins)

Net filtration pressure ​driving water and solutes across the glomerular membrane is affected by three pressures.

1. Glomerular capillary hydrostatic pressure

– (Pc, 45 mm Hg) in an outward direction

2. Hydrostatic pressure in the Bowman capsule

– (Pt, 10 mm Hg) inward

3. Colloid osmotic pressure of plasma in glomerular capillaries

– (πp, 28 mm Hg) inward

The equation is net glomerular filtration pressure = Pc – Pt – πp Net glomerular filtration pressure is normally about 7 mm Hg.

Glomerular versus systemic capillaries. T ​ he glomerular capillaries are much more permeable than average systemic capillaries. Approximately 180 L/day of fluid are filtered across glomerular capillaries, whereas only 4 L/day of fluid would have been filtered if these were systemic capillaries with their forces and properties. The ultrafiltration coefficient (Kf: membrane permeability × surface area) for glomerular capillaries is about 40 to 50 times greater than for systemic capillaries.

Permselectivity of Glomerular Membranes The permeability of glomerular membranes to solutes is dictated by the permselectivity of the glomerular filtration barrier.

Barrier layers ​ 1. Capillary endothelial cells 2. Endothelial basement membrane 3. Epithelial cells of the Bowman capsule

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Stones Any obstruction in the renal pelvis and ureters will increase hydrostatic pressure in the Bowman capsule. Kidney stones are one such obstruction and greatly reduce the GFR. Uric acid kidney stones may sometimes be dissolved by alkalinizing the urine with intake of potassium citrate.

Kidney stones that are < 0.5 in. (1.27 cm) in diameter can be fragmented by applying focused ultrasound waves (lithotripsy).

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Renal Physiology I Glomerular Filtration

Factors affecting permeability ​ 1. Electrical charge 2. Weight and size of particles that pass the barrier

– Less than 10,000 molecular weight passes through the filtration barrier.

– Particles that are 7.5 to 10 nm in diameter and are surrounded by positive charges pass through the “pores” or “channels.”

Barrier Damage Effects A damaged glomerular filtration barrier may allow more proteins to be filtered. Small molecules are less affected by a damaged barrier, as they are already highly permeable.

Nephrotic syndrome (nonspecific kidney damage) can be caused by many diseases, drugs, or allergies. Nephrotic syndrome results in severe loss of proteins into the urine and hypoproteinemia (decreased blood levels of protein, especially albumin).

The barrier is most permeable to small neutral or positively charged molecules and relatively impermeable to large negatively charged molecules, such as proteins.

Rate of Renal Plasma Flow The rate of RPF depends on the function of the heart and the cardiovascular system. If cardiac function is impaired, renal function will also be impaired. RPF is discussed in [XREF].

B.3 Hemodynamics of Glomerular Filtration Renal Oxygen Consumption The kidneys are perfused by more blood per unit of tissue weight than any major organ except the heart. They also consume more oxygen than any organ except the heart. High renal oxygen consumption reflects the amount of energy required for reabsorption of the filtered Na+. Renal arteriovenous (AV) oxygen content difference is lower than that of other organs. Renal venous blood is redder than that leaving other organs. Renal blood flow is far in excess of its basal oxygen requirements. Unlike other organs, most of the blood flow is not for intracellular metabolic needs, but for membrane transport processes.

Blood flow to the glomerulus ​is finely controlled by many factors that act on arterioles that are both afferent and efferent to the glomerulus. Regulation of glomerular filtration rate (GFR) is linked to regulation of renal plasma flow (RPF), because the flow of plasma to the kidneys determines the rate of filtration. The overall magnitudes of RPF and GFR are influenced by the following three factors:

1. Renal autoregulation 2. Autonomic innervation 3. Vascular resistance

Renal Autoregulation RPF and GFR remain almost constant over a wide range of mean arterial blood pressures (80–180 mm Hg) (Fig B.2). As blood pressure increases over this range, resistance in afferent arterioles increases proportionately to minimize large increases in RPF and GFR (Fig B.3). Autoregulation is an intrinsic property of the kidney, independent of neural influences and extrarenal humoral stimulation. Autoregulation helps to decouple the renal regulation of salt and water excretion from fluctuations in arterial blood pressure. There are two intrarenal mechanisms responsible for renal autoregulation:

1. Myogenic mechanism

– Intrinsic property of the afferent arteriolar smooth muscle

2. Tubuloglomerular feedback mechanism

– Feedback loop between the macula densa of the distal tubule and the afferent arteriole of the same nephron

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Glomerular Filtration I Renal Physiology

Fig B.3 ▶ Renal blood pressure.

0.6

3

Range of autoregulation

2

0.2

RBF 1

0

0

40

80

120

160

200

240

0

80 70 60 50 40 30 20 10 0

Re n

Mean pressure in renal artery (mmHg)

90 Mean pressure

0.4

100

al Int arter erl y ob .a Glo rte me ry, rul aff Eff ar .a ere ca rte pil r io nt l a le a rie Pe rte s rit r i ole ub ul Ve nu ar ca le pil lar Re ies na lv ein

4

Glomerular filtration rate (mL/min per g tissue)

Renal blood flow (mL/min per g tissue)

GFR

(mmHg)

Range of autoregulation

Fig B.2 ▶ Autoregulation of renal blood flow (RBF) and glomerular filtration rate (GFR).

Autonomic Innervation When sympathetic tone is increased, GFR tends to decrease less than RPF because both afferent and efferent arterioles are constricted. Pathologic conditions, drugs, and hormones may also reduce GFR by reducing filtration surface area and Kf (filtration coefficient).

Renal response to autonomic nervous system activation. ​ 1. Both afferent and efferent arterioles are innervated by sympathetic vasoconstrictor nerves.

2. Arterioles will constrict in response to sympathetic activation, such as a loud sound.

– Reduced renal blood flow, glomerular filtration, and urine flow

– Increased filtration fraction

3. There is no sympathetic activity in a denervated kidney.

– Na+ reabsorption decreases.

– Urine flow increases.

– Afferents from renal baroreceptors travel with sympathetic nerves to the central nervous system.

Vascular Resistance Even in the face of autoregulation of the kidneys as a whole, changes in RPF and GFR can occur through local changes in vascular resistance of afferent and efferent arterioles (Fig B.3). Resistance changes can be caused by actions of the autonomic nervous system and various vasoactive humoral agents.

1. Increase in sympathetic activity to the kidney

– Afferent and efferent arteriolar vasoconstriction

– Increased renal vascular resistance

– Decreased GFR

2. Decrease in sympathetic tone

– Decreased renal vascular resistance

– Increased GFR

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

B-11

B-12

Renal Physiology I Glomerular Filtration

Table B.1 ▶ Changes to Resistance in Renal Arterioles Change in resistance

Afferent arterioles

Efferent arterioles

Increase

Both RPF and GFR ↑

RPF ↓ GFR ↑

Decrease

Both RPF and GFR ↓

RPF ↑ GFR ↓

Vasoactive substances ​cause resistance changes in the arterioles.

1. Vasoconstrictors: catecholamines, angiotensin II, vasopressin, prostaglandins, and endothelin 2. Vasodilators: atrial natriuretic peptide (ANP), acetylcholine (ACh), adenosine, kinins, and nitric oxide (NO)

Effects of changes in resistance. ​Depending on which arterioles are affected, RPF and GFR change in different ways (Table B.1).

Resistance in Arterioles Because the afferent and efferent arterioles are in series, the total resistance to blood flow in the kidneys is the sum of their resistances.

Effects of altered resistance in efferent arterioles ​ 1. Increased resistance:

– Peritubular capillary blood flow increases.

– Reabsorption from the proximal and distal tubules increases (especially Na+).

2. Decreased resistance:

– Filtration fraction decreases.

– Hydrostatic pressure increases.

– Plasma colloid osmotic pressure decreases in the peritubular capillaries.

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Renal Tubular Transport I Renal Physiology

C-13

C. Renal Tubular Transport C.1 Active Tubular Transport The glomerular capillaries filter ~180 L of fluid a day into the nephrons, yet only ~1.5 L of urine a day are excreted. Thus, > 99% of what is filtered is reabsorbed from the renal tubules.

-

The renal transport for substances that are actively transported can be characterized by the capacity of the renal tubules to transport the substances at any one time. There is an upper limit for the rate of transport either in the reabsorptive or secretory direction.

Maximum Tubular Transport Capacity The maximum tubular transport capacity (Tm) is the highest attainable rate of tubular transport of any given solute. Transport systems exhibiting tubular transport maxima are known as Tm-limited transport processes. The existence of the Tm phenomenon can be explained in terms of saturation of the transport carriers and/or transport sites for a particular substance along the renal tubules. Substances with a reabsorptive Tm include phosphate and sulfate ions, glucose and other monosaccharides, many amino acids, and Krebs cycle intermediates.

Threshold concentration: reabsorption. ​The plasma concentration at which a reabsorbed solute reaches its Tm and begins to appear in urine is its threshold concentration and is characteristic for that substance. Glucose is not normally excreted, because all filtered glucose is reabsorbed. It will be excreted when it is at high plasma concentrations (> 300 mg/100 mL). This is indicative of diabetes mellitus (literally large volume of sweet urine). If the glomerular filtration rate (GFR) remains constant, the filtered glucose will be proportional to the plasma glucose concentration. As plasma glucose and consequently the filtered load increase,

1. Renal glucose transport sites become saturated.

2. Maximum transport rate of glucose is reached.

The amount of glucose not being reabsorbed will start spilling into the urine. Further increases in plasma glucose concentration will be followed by increases in the amount of glucose excreted. The maximum reabsorptive rate (Tm) for glucose is ~400 mg/min.

Threshold concentration: secretion. ​Some substances can also be secreted by Tm mechanisms: organic acids (e.g., uric acid and p-aminohippuric acid [PAH]), organic bases (e.g., creatinine and histamine), and other compounds not normally found in the body (e.g., penicillin and morphine). These secretory transport systems are important for the elimination of drugs and other foreign chemicals from the body. Secretory rates of these substances will increase as their arterial concentrations increase until their secretory Tms are reached. At concentrations above threshold,

1. Secretory rates reach a plateau.

2. Contribution of the secretion process to total urinary excretion decreases.

3. Amount excreted continues to increase slowly as the concentration in the glomerular filtrate increases.

Gradient-limited transport processes. F​ or some solutes, there is no definite upper limit for the rate of renal tubular transport (no Tm). Rates of transport are limited by the solute concentration gradient differences between the filtrate and the peritubular blood. Sodium reabsorption along the nephron is an example of a gradient-limited transport process.

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Peritubular Capillary Pressure Pressures in peritubular capillaries are comparable to capillaries in other organs. Capillary osmotic pressure is greater than interstitial os­motic pressure. This is due to the presence of plasma proteins.

Capillary osmotic pressure is greater than capillary hydrostatic pressure. This facilitates reabsorption of water from the renal tubule.

C-14

Renal Physiology I Renal Tubular Transport

C.2 Renal Clearance Renal clearance measures the efficiency of kidneys in removing a substance from plasma. It can be used to quantitatively measure the intensity of several renal functions, that is, filtration, reabsorption, and secretion. Renal clearance is defined as the theoretical volume of plasma from which a given substance is completely cleared by the kidneys per unit time. Each substance has a specific renal clearance value.

In general, for a given substance X, renal clearance of X is the ratio of its excretion rate to its concentration in plasma.

Calculation of Renal Clearance (a Modification of the Fick Equation) The equation for clearance of X is as follows: Cx = (Ux × V)/Px, where Cx is the renal clearance of the substance in mL/min; Ux and Px are the concentrations of substance X (mg/mL) in urine and plasma, respectively; and V is urine output or flow rate (mL/min).

Measurement of the factors for renal clearance ​ – V is obtained by measuring the volume of urine produced per unit time.

– Concentrations of substance X are measured in the urine sample (Ux) and in the plasma (Px).

Meaning of Renal Clearance Measurements Filtration, reabsorption, and secretion mechanisms all contribute to urinary excretion (or plasma clearance). The value for renal clearance of a substance gives information about how that substance is handled by the kidneys (Fig C.1). The direction and the rate of net renal tubular transport of a substance can be quantitatively determined using its renal clearance measurement.

Conservation of volume. ​At any one time, the total renal excretion of a substance must equal the algebraic sum of the three processes given in Table C.1.

Fig C.1 ▶ Clearance levels. PAH, p-aminohippuric acid.

Glucose Amino acids Na+, Cl–, etc.

Organic anions or cations (e.g., PAH and atropine, resp.)

1 Filtration

2 Filtration

+

+

Reabsorption

Secretion

Low excretion rate

High excretion rate

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

Renal Tubular Transport I Renal Physiology

Table C.1 ▶ Conservation of Volume Equations Total amount excreted = Amount filtered + Amount secreted – Amount reabsorbed Total amount excreted (Excretion rate, mg/min) = Ux ×.V˙

Ux = concentration of substance X in urine (mg/mL)

Amount filtered (Filtered load, mg/min) = Px ×.GFR

V˙ = urine flow rate (mL/min)

Net amount secreted (mg/min) = Amount excreted – Amount filtered

Px = concentration of substance X in plasma (mg/mL)

Net amount reabsorbed (mg/min) = Amount filtered – Amount excreted

GFR = glomerular filtration rate (mL/min)

Tm limitation. ​The renal clearance method can be used to determine whether or not renal transport of a substance is a Tm-limited transport process. This is done by constructing a renal titration curve, a combined plot of the filtered load, the urinary excretion rate, and the transport rate of substance X against the increasing plasma concentrations of X. The transport rate becomes constant at high plasma concentrations of X for a Tm-limited transport process.

Renal Clearance of Various Solutes Inulin ​is a nontoxic polysaccharide that is not bound to plasma proteins. Inulin is freely filtered at the glomerulus. It is neither reabsorbed nor secreted by renal tubules. The amount of inulin excreted in the urine is only the amount that is filtered at the glomerulus. The volume of plasma cleared of inulin per minute is equal to the volume of plasma filtered per minute, that is, glomerular filtration rate (GFR) (Fig C.2). Measurement of GFR, using the renal clearance of a substance such as inulin, is useful in evaluating renal disease.

Fig C.2 ▶ Inulin clearance = glomerular filtration rate (GFR).

H2O Urinary inulin concentration rises due to H2O reabsorption

No secretion No reabsorption

Inulin

Amount excreted/time = Urinary inulin concentration . (urine volume/time)

= =

Amount filtered/time = Plasma inulin concentration . (filtered volume/time)

· U ln (g/L) . VU (mL/min) = P ln (g/L) . GFR (mL/min)

GFR =

Uln . .

VU (mL/min) Pln

GFR » ~120 mL/min per 1.73 m2 body surface

TannerThies. Physiology – An Illustrated Review (ISBN 9781604062021), © 2010 Thieme Medical Publishers, Inc.

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C-16

Renal Physiology I Renal Tubular Transport

Creatinine ​is an end product of skeletal muscle creatine metabolism. Creatinine has a fairly constant concentration in plasma under normal conditions. The 24-hour creatinine clearance is used clinically to estimate GFR. Renal clearance of creatinine gives a slightly greater estimate of GFR than inulin, because it is secreted in small amounts in addition to being filtered and not reabsorbed. Creatinine is used rather than inulin, even though inulin is more accurate, because creatinine does not need to be administered as it is endogenously produced. Because plasma creatinine levels are stable, endogenous creatinine production normally equals creatinine clearance by the kidney.

plasma creatinine level and the magnitude of GFR. If GFR decreases to half of normal, creatinine production will exceed renal clearance, and serum creatinine will double. If GFR decreases to one fourth of normal, serum creatinine will increase 4 times. An increase in plasma creatinine concentration is an indicator of a decrease in GFR of similar proportion.

Urea ​is filtered, and some is passively reabsorbed (Fig C.3). Urea clearance is a poor estimate of GFR. It only works when urea reabsorption is a constant fraction of its filtered load. Plasma level of urea is used to estimate renal function by the same inverse relationship as serum creatinine. Serum urea level is expressed as blood urea nitrogen (BUN) concentration. When GFR falls, BUN concentration usually rises in parallel to serum creatinine. Urea clearance or BUN concentration is not a reliable indicator of the magnitude of GFR, because plasma urea concentration varies widely, depending on

1. Protein intake 2. Protein catabolism 3. Variable renal reabsorption of urea under different states of hydration affected by antidiuretic hormone (ADH) Fig C.3 ▶ Urea in the kidney.

100 % Urea concentration (mmol/L)

Urea 100 %

5 Impermeable to urea Passive reabsorption

Rest: 50 % Recirculation of urea

500

40 % FEurea

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Urea permeability subject to ADH control

The most clinically significant deficit in renal function with aging is the decline in GFR. This decline is due to the declines in renal plasma flow, cardiac output, and renal tissue mass.

Creatinine clearance, the index of GFR, also decreases with age. Plasma creatinine concentration remains constant with age. Decreased creatinine production from a reduction in muscle mass occurring with age is matched by decreased renal creatinine excretion.

Plasma creatinine concentration is not reliable as an estimate of renal function in elderly individuals.

Creatinine level versus glomerular filtration rate. ​There is an inverse relationship between

Circulates via countercurrent exchange in vasa recta

Decline in GFR

Renal Tubular Transport I Renal Physiology

C-17

PAH amount/time (mmol/min)

Fig. C.4 ▶ Secretion and excretion of p-aminohippuric acid (PAH).

1.00 Excreted PAH 0.75 Secreted PAH 0.50 Saturation 0.25

Filtered PAH

0

1

2

3

4

5

PAH concentration in plasma (free PAH) (mmol/L)

Glucose. ​The renal clearance of glucose is zero at normal plasma glucose concentration (80 mg/100 mL). Clearance is zero at up to 300 mg/100 mL, not because it is not filtered, but because all filtered glucose is reabsorbed in proximal tubules. If plasma glucose levels increase 4 times the normal,

1. Renal reabsorptive rate of glucose will reach its Tm (transport maximum).

2. Glucose excretion will increase until its clearance approaches GFR. At high plasma glucose concentrations, the majority of excreted glucose comes from its unreabsorbed filtered load.

P-aminohippuric acid. ​The renal clearance of p-aminohippuric acid (PAH) is greater than GFR, be-

cause it is filtered and also secreted into renal tubules (Fig C.4). More PAH is excreted than the amount originally filtered.

Renal clearance of PAH can be used to estimate the magnitude of renal plasma flow. All plasma-supplying nephrons can be cleared of PAH when PAH is below its secretory Tm. PAH will be completely cleared from the plasma by renal excretion during a single circuit of plasma flow through the kidney.

– Eighty-five to 90% of the total plasma flowing through the kidney is cleared of PAH. – Ten to 15% of the renal plasma flow is not filtered and bypasses renal tubules.

PAH clearance only approximates renal plasma flow. It is a measure of effective renal plasma flow (ERPF).

Effective renal blood flow (ERBF) ​is calculated from the effective renal plasma flow (ERPF) and hematocrit (Hct).

– Plasma is only about 55 to 60% of the blood.

– ERBF = ERPF/(1 – Hct).

At higher plasma PAH concentrations, renal secretory transport of PAH reaches its Tm. Then the contribution of secretion to renal clearance of PAH decreases. As plasma PAH levels increase, renal clearance of PAH decreases toward the value of GFR.

C.3 Mechanisms of Renal Tubular Transport The Na+–K+ adenosinetriphosphatase (ATPase) pump uses energy to establish a gradient for transport.

Other specific membrane symporters and carriers facilitate transport of various substances. Renal tubular transport of solutes requires transepithelial movement of solutes at both the luminal and basolateral membranes. Renal tubular transport requires the transport systems at both membranes to work together in series.

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Diabetes The high plasma glucose levels in diabetes exceed its Tm, so glucose in the collecting ducts causes an osmotic diuresis.

Renal Physiology I Renal Tubular Transport

C-18

Sodium-Dependent Secondary Active Transport Organic substances including glucose are reabsorbed in proximal tubules by Na+-dependent secondary active transport. Na+–K+ ATPase in the basolateral membranes of renal tubule cells establishes an electrochemical gradient for Na+, – Extruding Na+ from cells – Pumping K+ across the basolateral membrane

Glucose. ​The electrochemical gradient for Na+ provides the energy for the uphill glucose transport into cells across the luminal brush border membrane. Glucose accumulates within the cells. Glucose leaves cells across the basolateral membrane by facilitated diffusion. The transport systems for glucose on both membranes are specific for the D-forms of sugars. They are inhibited by D-sugar analogues and specific inhibitors.

Other organic solutes (​ phosphate, amino acids, Krebs cycle intermediates, and metabolic intermediates) are reabsorbed from proximal tubules by cotransport with Na+ across the luminal membrane (Fig C.5). They are transported by facilitated diffusion across the basolateral membrane.

P-aminohippuric acid ​is taken up into the proximal tubule cells from peritubular capillary blood across the basolateral membrane. It moves against its electrochemical gradient by an active transport mechanism specific for organic anions. This is called the PAH di- and tricarboxylate transport mechanism, through which PAH

1. Accumulates within proximal tubule cells.

2. Is secreted into luminal fluid by facilitated diffusion.

Transport of Ions and Water Sodium ​ions are actively reabsorbed along the whole length of the renal tubule (Fig C.6). Na+ moves from the tubular lumen into cells down its electrochemical gradient by several mechanisms.

1. Cotransport with other solutes (e.g., glucose and Cl–) 2. Countertransport (exchange) with H+ 3. Simple diffusion via Na+ channels -

Fig. C.5 ▶ Reabsorption of organic substances. ATP, adenosine triphosphate.

Lumen

Cell

Fig C.6 ▶ Overview of important transport processes along the nephron.

Blood

Secondary active

NH3

+

Na

x

b

a

x

ATP

x Na+

+

Na

Brush border membrane

x

Glucose, amino acids (several systems), phosphate, lactate, sulfate, dicarboxylates

Na+: Primary active Cl– : Secondary active

Primary active and passive

Glucose, amino acids, phosphate, lactate, sulfate Secondary active

H+

NaCl

Na+ Ca2+ K+

Ca2+

Luminal Na+ symport

b

Passive carrier transport

Na+

Na+: Primary active Cl– : Secondary active

NaCl

Urea Metabolites, Cl– H2O drugs, PAH

Ca2+ Mg+

Basolateral membrane a

K+

Pink – Active reabsorption Yellow – Passive reabsorption Blue – Active transport secretion Green – Passive cellular secretion Purple – Active cellular secretion

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K+ H+

Na+ Cl– Urea

Cl– H2O

Renal Tubular Transport I Renal Physiology

After Na+ enters cells, it is actively transported across the basolateral membrane by the Na+–K+ ATPase system.

Chloride ​ions are mostly passively reabsorbed. The concentration gradient favors the movement of Cl– from lumen to peritubular blood. This gradient is established by NaHCO3 and water.

Potassium ​ions are reabsorbed in the proximal tubule and early distal tubule by 1. Active transport at luminal membranes (H+–K+ ATPase) 2. Passive outflux at peritubular membranes 3. Paracellular (between cells) pathway Water ​is passively reabsorbed by osmosis in response to solute osmotic gradients (Fig C.7). Antidiuretic hormone (ADH) affects permeability of the collecting duct.

Hydrogen ​ions are generated from carbonic acid within renal cells. Carbonic acid is formed by hydration of CO2 within renal cells in a reaction catalyzed by carbonic anhydrase. H+ is secreted across the

luminal membrane by

1. Secondary active transport coupled to Na+ entry (Na+–H+ exchange) 2. Primary active transport (H+ ATPase) In the distal tubule, secreted H+ (via H+ ATPase) combines with other urinary buffers (HPO42– and NH3).

The products are then excreted in the urine.

Secreted H+ also reacts with filtered HCO3– in the proximal tubular lumen to form carbonic acid with the

aid of carbonic anhydrase present on the external luminal membranes of proximal tubule cells.

Carbonic acid in proximal tubule fluid dissociates into CO2 and H2O.

CO2 diffuses back into proximal tubule cells and is rehydrated in the cells to carbonic acid.

Carbonic acid dissociates to HCO3– and H+.

HCO3– crosses basolateral membranes into peritubular blood.

H+ is resecreted into the tubular lumen.

Secreted H+ is converted into H2O in cells of the proximal tubule, and filtered HCO3– from proximal

tubule fluid is transferred to peritubular blood.

H2O follows NaCl, etc.

Plasma water

Water follows NaCl

H2O permeability subject to ADH control

GFR = 100%

65% Rest: 25%

220

Cortex

290 mOsm/kg H2O

Fig C.7 ▶ Water reabsorption and excretion. ADH, antidiuretic hormone; GFR, glomerular filtration rate.

NaCl

High osmolality of interstitium: H2O outflow 10%

Watertight

600

Rest: 35%

1200

Outer medulla

ADH

Inner medulla

1.

2.

3.

4.

5.

6.

High H2O permeability in antidiuresis

0.5 %

Maximum antidiuresis

FE H2O Maximum

5 % and water diuresis more

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C-19

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Renal Physiology I Renal Tubular Transport

C.4 Transport Processes along the Nephron Segments of the nephron are characterized by distinct combinations of permeabilities and electric and osmotic potentials. As a result, substances are secreted or resorbed in specific segments of the nephron.

The key segments are the proximal tubule, the thick ascending limb of the loop of Henle, and the late distal tubule and collecting duct.

Proximal Tubule Glomerular filtrate. ​Sixty-five to 90% of the glomerular filtrate is normally reabsorbed in the proximal tubule. The reabsorption is isosmotic. Reabsorption of Na+ and other solutes tends to decrease osmolality of tubular fluid and raise osmolality of surrounding interstitial fluid transiently.

Water ​is reabsorbed in response to the osmotic gradient in the same proportion as solutes. The proximal tubule has relatively high permeability to water, resulting in the reabsorbed fluid moving from interstitial space into peritubular capillaries by bulk flow. This is caused by the net balance of hydrostatic and oncotic pressures acting across the capillary walls.

Potential difference. ​There are small transepithelial potential differences across the tubule. In the early part of the proximal tubular lumen, the potential difference is slightly negative (–4 mV). In the late part of the proximal tubule, the potential difference becomes slightly positive (+3 mV).

Reabsorbed substances. ​Na+, K+, Ca2+, Cl–, HCO3–, phosphate, sulphate, and water are reabsorbed.

Na+–K+ ATPase in the peritubular membrane transports Na+.

– Na+ travels across the luminal membrane by passive transport.

– K+ is reabsorbed passively by its concentration gradient from tubule to capillary.

If this ATPase is inhibited, less Na+ transport will cause decreased secondary transport of – Glucose, amino acids, and lactate – Ions like K+, Cl–, and Ca2+ – HCO3– reabsorption by an H+–Na+ antiporter

– Urea and Cl– are reabsorbed by passive diffusion due to concentration differences.

Secreted substances ​ – Organic acids and NH3

– Hydrogen ions are actively secreted against a concentration gradient of 25:1.

Glomerulotubular balance. ​Under steady-state conditions, a relatively constant fraction of the filtered Na+ is reabsorbed in the proximal tubule despite variations in glomerular flow rate (GFR). The absolute rate of Na+ reabsorption in the proximal tubule will increase proportionately with the increase in GFR or Na+ filtered load. This helps to minimize changes in Na+ excretion that follow changes in GFR.

Loop of Henle The two parts of the loop of Henle have different characteristics.

1. Descending limb

– Relatively permeable to water

– Poorly permeable to solutes like Na+, Cl–, and urea

– Less relevant to transport in the nephron

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Renal Tubular Transport I Renal Physiology

2. Thick ascending limb

Diuretics

– Impermeable to water

– Ions and salts are reabsorbed without water

– Primary site for dilution of urine

– Transepithelial potential difference is 10 mV lumen positive

Reabsorbed substances. ​There is net transepithelial reabsorption of Na+, Cl–, and K+. Na+, K+, and Cl– enter cells together by a secondary active transport process (cotransport of K+ and Cl– with Na+). Na+ is transported out of cells at the peritubular side by an Na+–K+ ATPase. Cl– leaves cells on the peritubular side by a passive mechanism. Net K+ reabsorption in this segment is very small compared with net reabsorption of Na+ and Cl–. The thick ascending loop of Henle is also the major site for Mg2+ reabsorption.

This occurs paracellularly (between cells) through tight junctions. Reabsorption of ions and water in this segment produces high ion and osmolar concentration gradients between the lumen of the ascending limb of the loop of Henle and the peritubular fluid (medullary interstitium).

Late Distal Tubule and Collecting Duct Water reabsorption ​is dissociated from salt reabsorption in these segments. The permeability to water of the distal nephron is under the control of antidiuretic hormone (ADH).

Sodium reabsorption. T ​ he peritubular membrane has an Na+–K+ ATPase. Na+ moves passively through the luminal membrane. Na+ concentration in the tubular fluid can be reduced to zero. Aldosterone stimulates Na+ reabsorption.

Cl– reabsorption ​is mostly passive through the paracellular pathway.

Potassium secretion. ​K+ is secreted in distal tubules and cortical collecting ducts by passive entry of K+ from cells into the lumen.

The luminal membrane is more permeable than the peritubular membrane. Because most filtered K+ is reabsorbed in the proximal tubule, the rate of K+ excretion is proportional to its secretory rate in the distal nephron.

The rate of K+ secretion is controlled by the following factors:

1.

2.

3.

4.

C-21

Cell K+ content (depending on K+ intake and acid–base balance) Tubular fluid flow rate (depending on Na+ excretion rate) Transepithelial potential difference (influenced by K+ intake and Na+ excretion rate) Aldosterone, which stimulates K+ secretion in the cortical collecting duct

If dietary K+ is elevated for a few days, the area of basolateral membrane of cortical collecting ducts will increase. This facilitates secretion of K+ into the ducts. If plasma K+ (hyperkalemia) were to stay elevated, nerves and muscles would be more excitable.

Ca2+ reabsorption ​is facilitated by parathyroid hormone (PTH) and the activated form of vitamin D in the distal tubule. PTH inhibits phosphate reabsorption in the proximal tubule.

Hydrogen ions ​ are actively secreted against a concentration gradient of 1000:1 via an H+–ATPase system.

– Tubular fluid can be significantly acidified in the distal nephron – Aldosterone stimulates H+ secretion.

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Loop diuretics inhibit Na+ and Cl– reabsorption in the thick ascending limb, which causes increased urine flow and decreased osmolality in the medullary interstitium. An example is furosemide, which is potent because it acts where one fourth of filtered Na+ is reabsorbed.

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Renal Physiology I Water/Solute Regulation

D. Water/Solute Regulation D.1 Concentration and Dilution of Urine The kidneys are able to produce urine that is either more concentrated or more diluted than plasma.

The range of urine concentrations is from 50 to 1200, or slightly more mOsm/kg H2O. The ability of the

kidneys to concentrate urine makes it possible for a person to survive with minimal or excessive water intake. Antidiuretic hormone (ADH) regulates the water content in the urine through its effects on the permeability of the distal tubule and collecting duct.

Countercurrent System The countercurrent multiplication system in the loop of Henle conserves water. The hairpin turn and close apposition of descending and ascending limbs of the loop of Henle in the medulla of the kidney provide the proper structure (counterflow) for the operation of a countercurrent multiplier (Fig D.1).

Fig D.1 ▶ Countercurrent systems.

H 2O 600

600 600

800

600

600

800 800

800 1000

800 1000

1000 1000

mOsm/kg H2O

1000

1200 1200

Countercurrent exchange (water) in loop (e.g., vasa recta) Watertight

H2O 400

400

400

200

600

800

800

600

400

600

800

Medulla

NaCl

NaCl

1000 1000 1000

600 NaCl

NaCl

800

Cortex

NaCl

NaCl

600

400

800

1000

1200 1200 Countercurrent multiplier (Henle loop)

Vasa recta Collecting duct

Henle loop

Countercurrent systems in renal medulla

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Epithelial permeability characteristics. ​The epithelia of the loop of Henle have special permeability characteristics.

1. Descending limb of the loop of Henle is

– Highly permeable to water

– Poorly permeable to solutes

2. Ascending limb is

– Relatively impermeable to water

– Permeable to Na+ and Cl–

3. Thick ascending limb

– Na+ and Cl– are actively reabsorbed in the thick ascending limb of the loop of Henle. These permeability and transport characteristics allow the ascending limb to separate its solute transport from water transport.

Horizontal osmotic gradient. ​The separation of solute and water transport creates a horizontal osmotic gradient between tubular fluid in the ascending limb and that in the descending limb. This horizontal osmotic gradient is then multiplied vertically along the length of the descending loop of Henle.

This system generates an osmotic gradient within the tubular fluid of the descending limb from ~300 mOsm/kg H2O at its start to 1200 mOsm/kg H2O at the bend of the loop.

Medullary interstitium. ​A concentration gradient is established within the medullary interstitium (extracellular fluid) from the renal cortex to the inner renal medulla.

1. Nephron segment is highly permeable to water.

2. Medullary interstitium is equilibrated with the fluid in the descending limbs.

3. Highest concentration is at the tip of the papilla.

Sequence of events ​as fluid flows through the loop of Henle: 1. Isosmotic tubular fluid from the proximal tubule enters the descending limb of the loop of Henle.

2. Fluid becomes more concentrated as it moves toward the bend of the loop.

– Fluid in the descending limb equilibrates osmotically with fluid within the medullary interstitium.

– Extracellular fluid is more concentrated toward the bend of the loop.

3. Concentrated fluid at the bend of the loop then becomes progressively more diluted as it flows through the ascending loop of Henle.

– Na+ and Cl– can be reabsorbed without water following.

– Tubular fluid is hyposmotic (100 mOsm/kg H2O) at the end of the loop.

– Hyposmotic in antidiuresis when urine flow is slow

Role of the Vasa Recta The vasa recta are hairpin capillary beds that are located beside the loops of Henle and collecting ducts.

They are – Formed from efferent arterioles of juxtamedullary glomeruli.

– Permeable to solutes – Permeable to water similar to other systemic capillaries The vasa recta act as a passive countercurrent exchanger system.

1. Solutes are transported out of the ascending loop of Henle.

2. Solutes diffuse down their concentration gradients into the descending vasa recta.

3. Blood in the descending vasa recta becomes progressively more concentrated as it equilibrates with the corticomedullary osmotic gradient.

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D-23

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Renal Physiology I Water/Solute Regulation

Ascending vasa recta. ​In the ascending vasa recta, solutes diffuse back into the medullary interstitium, eventually entering the descending vasa recta. Blood leaving the renal medulla becomes progressively less concentrated as solutes return to the inner medulla. Solutes recirculate within the renal medulla, keeping the solute concentration high within the medullary interstitium.

Passive equilibration. ​The blood within each limb of the vasa recta is passively equilibrated with the preexisting medullary osmotic gradient at each horizontal level. This helps maintain the medullary osmotic gradient necessary for the production of hyperosmotic urine. If blood flow is too rapid in the vasa recta, the osmotic gradient will decrease.

Role of Urea Urea and NaCl are the two major solutes within the medullary interstitium. Filtered urea undergoes net reabsorption passively in the proximal tubule.

Concentration. ​Urea concentration at the end of the proximal tubule is approximately twice that of plasma because of water reabsorption. The concentration in the tubular fluid is further increased in the thin loop of Henle. More urea is secreted into the tubular fluid from the medullary interstitium. Urea concentration in the tubule fluid remains high until the fluid flows through collecting ducts.

Medullary recycling of urea. ​The thick ascending loop of Henle and distal tubule have low permeability to urea, whereas collecting ducts are more permeable to urea. Urea therefore diffuses out of the medullary collecting ducts. It enters the interstitium and vasa recta, as well as reentering the descending loop of Henle.

Urea constitutes ~40% of papillary osmolality in the presence of ADH (antidiuresis).

1. ADH increases the permeability of medullary collecting ducts to urea as well as to water.

2. Less than 10% of medullary interstitial osmolality is due to urea in the absence of ADH (water diuresis).

The medullary recycling of urea helps establish the osmotic gradient within the medulla.

1. There is less energy expenditure (urea transport is passive).

2. Water is conserved.

Measurement of Concentrating and Diluting Ability Quantitative assessment. T ​ he simplest method is to measure maximum and minimum urine osmolality. The more practical, common method is to quantify water excretion. This quantification is based on the concept that urine flow can be divided into two components.

1. Urine volume needed to excrete solutes at the same concentration as that in plasma (volume of isosmotic urine = osmolal clearance [Cosm])

2. Volume of water that is free of solutes (free water) Solute-free water. ​The kidney generates solute-free water in the ascending limb of the loop of Henle by reabsorption of Na+ and Cl– without water. Solute-free water can be either removed or added back to plasma by excreting dilute or concentrated urine.

Free water clearance. (​ CH2O) is defined as the amount of distilled water that must be subtracted from or added to the urine (per unit time) to make that urine isosmotic with plasma.

CH2O = urine flow rate – osmolal clearance Osmolal clearance = urine flow rate 3 urine osmolality/plasma osmolality

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Table D.1 outlines urine concentration effects for the three types of urine.

Table D.1 ▶ Urine Concentration Urine type

CH2O

Results

Hyposmotic

Positive

Free water is removed from body

Hyperosmotic

Negative

Solutes are removed without water, or free water is added to body

Isosmotic

Zero

None

D.2 Regulation of Water and Salt The kidneys regulate extracellular fluid volume and osmolarity by altering – Amount of water excreted – Amount of sodium excreted The kidneys work with the cardiovascular and endocrine systems to ensure that the cells of the body are bathed in salty fluid of relatively constant composition (Fig D.2).

Water Balance Mechanisms. ​The regulation of body water depends on the balance between the rates of water movement into and out of the body. Two major and one minor mechanism are responsible for water balance.

1. Thirst

– Controls water intake

2. ADH

– Regulates urinary water excretion

3. Perspiration

– Adds to water (and salt) excretion Fig D.2 ▶ Hypertonic and hypotonic cell environments.

1

Water deficit, salt excess

Water excess, salt deficit

2

Hypertonic environment

Hypotonic environment

H2O H2O

= solute particles

Cell shrinks

Cell swells

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Renal Physiology I Water/Solute Regulation

Table D.2 ▶ Hyposmotic and Hyperosmotic Urine Type

Hyposmotic

Hyperosmotic

Conditions

Hydration

Dehydration

Concentration

Low

High

Permeability of distal tubule and collecting duct

Low

High

Water resorbed

Low

High

Salts resorbed

Normal

Low

Comparison to distal tubular fluid

Remains hyposmotic

Isosmotic

Typical urine concentration

100 mOsm/kg H2O

1200 mOsm/kg H2O

Factors Affecting Water Balance Diabetes Mellitus Osmotic diuresis is the loss of water in the urine due to the presence of unreabsorbed solutes. Patients with diabetes mellitus have sugar in their urine that “carries” water with it. Net reabsorption of Na + is reduced, because there is a larger gradient for passive Na+ diffusion from the interstitium to the proximal tubular lumen.

Antidiuretic hormone ​(vasopressin) is a peptide hormone synthesized in hypothalamic neurons of the supraoptic nucleus. It is

1. Transported in axons to the posterior pituitary 2. Stored in nerve terminals until released by conducted action potentials 3. Released into the pituitary circulation and travels in the blood Plasma osmolality ​is the most important regulator of ADH release. Total solute concentration within

body fluids is significantly affected by water gain or deficit (Fig D.3). The circulating level of ADH regulates the amount of water reabsorption from distal tubules and collecting ducts by the following sequential negative-feedback control system:

1.

2.

3.

4.

5.

6.

Diabetes Insipidus Diabetes insipidus occurs if ADH is not synthesized or released or if its receptors are not functioning. Water is not reabsorbed from the distal tubules and collecting ducts.

ADH may not be available if the posterior pituitary is damaged.

In the absence of ADH to promote water reabsorption from the collecting duct, the patient produces a water diuresis with hypotonic urine.

Water Intoxication Excessive voluntary drinking of water can decrease plasma osmolality to dangerous levels.

For example, a person “purging” their gut by drinking 4 L of plain water will experience hyponatremia, low plasma [Na+]. The kidneys excrete very dilute urine, but some electrolytes are lost as well.

Increase in plasma osmolality Increase in ADH Stimulation of hypothalamic osmoreceptor neurons Further increase in ADH Increase in H2O reabsorption Dilution of plasma

Blood volume. ​A decrease in blood volume stimulates ADH release. Atrial baroreceptors normally inhibit ADH release. A decrease in atrial pressure counteracts this inhibitory effect (disinhibition).

Mechanism of action of ADH:

1.

2.

3.

4.

5.

Binds to specific receptors on basolateral membranes of epithelial cells of the distal nephron Acts on distal tubules, especially collecting ducts Activates an adenylate cyclase second messenger system to insert water pores into membranes Increases the permeability of luminal membranes to water Increases plasma volume

Water Intake Water intake is regulated through a thirst center located in the hypothalamus. Thirst is stimulated by both an increase in plasma osmolality and a reduced extracellular fluid volume. These are the same stimuli that affect ADH secretion. The hormone angiotensin II is also an important stimulus for thirst.

Water Loss Dehydration is the loss of water, with concentration of salt in the remaining body fluids (Fig D.4).

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Water/Solute Regulation I Renal Physiology

Water deficit Osmolality

1

2

Water excess Osmolality

Atrial pressure

Thirst AT II

ADH

H2O reabsorption

H2O reabsorption

Posterior lobe of pituitary

decreases

Water excretion:

increases

3

Water deficit

Salt deficit

H2O

ECR

ICR

H2O

Intake of seawater, steroid hormones, increased aldosterone, infusion of hypertonic saline solution

2

Excessive fluid intake or ADH secretion, gastric lavage, infusion of glucose solution

1 Isosmotic volume deficit

Heart failure, kidney disease

Vomiting, diarrhea, perspiration, aldosterone deficit

Normal

Perspiration, hyperventilation, osmotic diuresis, ADH deficit (diabetes insipidus)

Fig D.4 ▶ Disturbances of salt and water homeostasis. ADH, antidiuretic hormone; ECR, extracellular; ICR, intracellular.

Vomiting, diarrhea, diuretics, blood loss, burns

.

Fig. D.3 ▶ Regulation of water balance. ADH, antidiuretic hormone; AT II, angiontensin II.

4

5

6

Water excess

Salt excess

Isosmotic volume excess

H2O

H2O

Salt

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Renal Physiology I Water/Solute Regulation

Sweating ​can increase from 0.1 to 5 L/hour in a bout of heavy exercise. Sweat is hyposmotic, so body fluids become more hyperosmotic.

Diarrhea ​causes isosmotic loss of both water and solutes. Kidneys produce a small volume of very concentrated urine to conserve water.

Hemorrhage o ​ r excessive blood loss is isosmotic. Compensations include increased heart rate and a shift of fluid from interstitial to plasma. There is increased secretion of renin and ADH and production of angiotensin II. Best replacements are also isosmotic, such as blood, plasma, and normal saline (0.9% NaCl).

Loss of water without ions. G ​ iving distilled water intravenously lyses red blood cells due to osmotic forces.

1. Loss is prevented by giving a 5% glucose solution with normal osmolality 2. Body metabolizes the glucose quickly, leaving an increase in water without ions.

Sodium Balance Sodium is the most abundant solute in extracellular fluid (ECF). The status of Na+ balance is an important factor, as it determines

1. Volume of the ECF compartment 2. Long-term regulation of blood pressure Sodium concentration is regulated through

1.

2.

3.

4.

5.

Water balance (indirectly) Glomerular filtration Change in volume of ECF Tubular reabsorption Renin–angiotensin–aldosterone system

Regulation of sodium through water balance. ​Sodium and water balance are linked because whenever water is added, sodium concentration decreases, and vice versa. Plasma [Na+] is first regulated by conservation or excretion of water. Na+ is the primary osmotic component of ECF. Osmoreceptors and ADH regulate plasma [Na+] indirectly.

Renal regulation: glomerular filtration and tubular reabsorption. T ​ he kidneys regulate sodium concentration balance and thereby ECF volume. The amount of Na+ excretion is regulated according to Na+ intake. Excretion is the result of glomerular filtration and tubular reabsorption.

Glomerular filtration ​occurs when the plasma concentration of sodium is too high. A slight increase in plasma osmolarity (usually Na+ and Cl–) will cause a 100-fold increase in the concentration of ions in the urine. Approximately 180 L/day of glomerular filtrate are concentrated into 1.5 L/day of urine.

Autoregulation ​of the glomerular filtration rate (GFR) automatically prevents excessive changes in the rate of Na+ excretion in response to spontaneous changes in blood pressure. If the kidneys did not autoregulate, then increased blood pressure would increase renal blood flow and GFR. This would filter more Na+ and give less time for Na+ reabsorption in the renal tubule, increasing Na+ excretion.

Tubuloglomerular feedback ​adjusts sodium reabsorption to match the GFR and compensates for changes in the filtered load of Na+ due to acute changes in GFR when Na+ and volume are normal. Macular densa cells in the distal tubule signal the adjacent afferent arteriole to constrict after GFR increases, thereby decreasing GFR. If glomerulotubular balance were abolished,

1. Na+ excretion would vary more directly with GFR.

– Increased GFR increases Na+ excretion, so Na+ intake would need to increase.

2. Na+ balance and ECF volume would be restored.

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Tubular reabsorption of Na+. ​The kidneys conserve Na+ by normally reabsorbing 99.4% of filtered Na+. Aldosterone stimulates Na+ reabsorption in the collecting ducts by

1. Increasing the permeability of the luminal membrane 2. Increasing permeability to K+ Aldosterone secretion is increased in response to

1. Decreased ECF volume 2. Increased plasma K+ concentration by a direct action in the adrenal cortex 3. Increased plasma angiotensin II concentration

Renin–Angiotensin–Aldosterone System This messenger system is the most important regulator of Na+ balance.

Location. ​Chemicals in the renin–angiotensin cascade are synthesized in specific locations.

1. Renin is synthesized in the juxtaglomerular cells of the renal afferent arterioles.

2. Angiotensinogen is an inactive plasma protein synthesized in the liver.

Action ​ 1. Renin acts on angiotensinogen to form angiotensin I in the bloodstream (Fig D.5).

2. Angiotensin I is converted to angiotensin II by angiotensin-converting enzyme (ACE).

– ACE is located primarily in pulmonary capillary endothelium.

– ACE activity is also present in capillary endothelial cells.

3. Angiotensin II stimulates the release of aldosterone, which is synthesized in the zona glomerulosa of the adrenal cortex.

Fig D.5 ▶ Renin–angiotensin system. GFR, glomerular filtration rate; RBF, renal blood flow.

Normalization of plasma volume and blood pressure

Renin secretion

Acute drop in: Plasma volume and blood pressure

Renin 4 31 11 12 1

1 2 3 4 5 6 7 8 9 10

Angiotensinogen

1 2 3 4 Asp Arg Val Tyr

5 Ile

6 7 8 His Pro Phe

0 9 1u His Le

Angiotensin I Converting enzyme 1 2 3 Asp Arg Val

4 Tyr

5 Ile

6 7 8 His Pro Phe

Angiotensin II Craving for salt Adrenal cortex

Thirst

GFR and RBF

Aldosterone

General vasoconstriction

Reduced salt and water excretion Increased fluid and salt intake

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Renal Physiology I Water/Solute Regulation

Renin release factors ​ultimately influence renal excretion of Na+. Renin release is 1. Increased by low blood pressure 2. Decreased by increased stretch of right atrial mechanoreceptors Fight or Flight The sympathetic nervous system is activated by stress, producing the “fight or flight” response. Renal blood flow is maintained during such responses by autoregulation.

Cardiac output and blood pressure increase to supply increased blood flow to active skeletal muscles. Renal function still must be maintained, especially to deal with metabolites and H+ from muscle activity.

Hypertension Hypertension can result if the kidneys lose their sensitivity to increased blood pressure. The “pressure diuresis” hypothesis suggests that high blood pressure causes less excretion of Na+ than normal. One treatment for hypertension is to reduce the plasma [angiotensin II]. This is done by giving drugs that inhibit the action of ACE.

The most important stimulus for renin release is depletion of the ECF compartment volume. This response is detected by baroreceptors in the renal afferent arterioles. Increased renal sympathetic nerve activity and angiotensin II levels directly increase Na+ reabsorption to increase ECF volume.

Natriuretic hormones, ​a humoral Na+-losing system, act to increase renal excretion of Na+. One such hormone is atrial natriuretic peptide (ANP). ANP is released from the atria in response to stretch of the atria. This stretch is due to an expansion of the ECF compartment. ANP increases Na+ excretion by

1. Raising GFR 2. Reducing tubular reabsorption of Na+ in collecting ducts ANP also inhibits renin and aldosterone secretion.

Other influences on Na+ reabsorption. ​Renal interstitial hydraulic pressure can also influence Na+ reabsorption. Higher pressure decreases Na+ reabsorption. Renal tubular Na+ reabsorption increases in disease states when there is a decrease in the renal effective ECF volume.

Sodium Retention Diseases such as cirrhosis of the liver and heart failure cause Na + retention. This in turn causes generalized edema. Diuretics are given to increase excretion of both Na+ and excess fluid.

Response to a large Na+ load In response to ingesting a large amount of sodium (6000 mg [103 mEq]), the kidneys will quickly conserve water to maintain osmolality, although the osmolarity of both the ECF and the ICF will increase. [XREF Fig. 175 E6] Excretion of the excess Na+ is much slower than conserving water, but the kidneys do both. Eventually, the Na+ load will be excreted as more hypertonic urine.

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Acid–Base Balance I Renal Physiology

E-31

E. Acid–Base Balance E.1 Nonrenal Mechanisms Acid–base balance, or the concentration of H+ in the extracellular fluid (ECF), is tightly regulated.

– Mean pH of arterial blood is 7.40 or [H+] ~40 nmoles/L – pH is controlled within a small range, 7.37 to 7.42 (+ or – 5% from the mean value) This delicate balance is threatened continuously by additions of extra acids or bases to body fluids from metabolic processes (Fig E.1). Table E.1 outlines the mechanisms of acid–base balance.

Fig E.1 ▶ Factors affecting blood pH.

Dietary intake and metabolism

Respiration Cellular respiration produces some 20,000 mmoles of CO2 (or H2CO3, volatile acid) daily.

This is a tremendous acid load, but it is continuously eliminated by the lungs, so pH is not changed under normal conditions. The lungs are 200 times as effective in excreting acid (as CO2) as the kidneys.

The kidneys excrete about 60 mmoles of H+ per day.

Acids and Bases

HCO3–

H2O

H+

CO2

HCO3–

CO2

Nonbicarbonate buffers Hemoglobin, plasma proteins, phosphates, etc.

OH–

CO2

Henderson-Hasselbalch equation

pH

– log [H+] =

[HCO3–] = pKa + log ______ [CO2]

CO2 Respiration 2 HCO3– + 2 NH4+

Urea, etc.

Liver Kidney

HCO3–

NH4 + or

H+ as H2PO4 –

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Nonvolatile acids or fixed acids come from protein diets (e.g., H2SO4 and H3PO4). Acids measure about 50 to 100 mEq of H+ added per day. Bases come from vegetarian diets (e.g., lactate and citrate). Fixed acid concentrations may also rise during exercise or many pathological conditions.

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Renal Physiology I Acid–Base Balance

Table E.1 ▶ Mechanisms of Acid–Base Balance Type

Action

Response time

Effectiveness

Chemical buffering

Maintains pH

Seconds

Both acid and base

Respiratory

Excretes acid

Minutes

Acid only

Renal

Excretes acid and base

Days

Base more than acid

Buffering Systems Buffers Buffers are chemicals that prevent wide swings in pH by combining or releasing H+.

Thus, the pH change will be moderated in response to the addition of H+ or base to the body.

pK pK is calculated from the dissociation constant of an acid or a base. It is the pH at which a buffer pair is most effective.

Changes in pH are buffered by systems within the body. The most important buffers in the body are phosphate, protein, and bicarbonate buffers.

Phosphate buffer. ​(HPO42–/H2PO4–) has a pK of 6.8.

– pK is close to 7.4 – Concentration is low – Contributes little to the buffering capacity of the ECF – Important chemical buffer within intracellular fluid

Protein buffers ​include various intracellular proteins and proteins in blood. Plasma proteins and hemoglobin are strong buffers.

– Abundant in blood – Broad-ranged pK values Hemoglobin helps buffer H+ generated from CO2 during CO2 transport in blood from tissues to the lungs.

The buffering capacity of hemoglobin is further enhanced during the process of deoxygenation. Deoxygenated hemoglobin is less acidic than oxygenated hemoglobin. It can act as a base and accept extra H+ formed from CO2 within red cells during the passage of CO2 from tissues to the lungs. The enhanced

buffering capacity of deoxygenated hemoglobin prevents significant pH changes between arterial and venous blood during CO2 transport.

Buffer Pair A buffer pair is an acid or base and its salt. The ratio of the two concentrations and their pK determine the pH of the buffer.

Bicarbonate buffer. ​(HCO3–/H2CO3 or HCO3–/pCO2) is the most important physiological buffer of ECF (Fig E.2) even though its pK of 6.1 is far from 7.4 due to its high concentration in plasma (24 mM).

The buffer pair can be tightly regulated, CO2 by the lungs and HCO3– by the kidneys. All buffer pairs in

plasma are in equilibrium with the same concentration of H+. A change in the buffering capacity of the

entire blood buffer system will be reflected by a change in the buffering capacity of only one buffer pair (isohydric principle). The acid–base status or pH of ECF can be evaluated by examining only the bicarbonate buffer system (Fig. E.2).

Utilization of Various Buffers Addition of buffer to extracellular fluid. W ​ hen the acid–base disturbance is derived from the addition of the bicarbonate buffer pair to ECF, > 95% of the buffering will be done by proteins and phosphates within cells, because the HCO3– buffer system cannot buffer itself.

Addition of acids or bases to extracellular fluid. W ​ hen the acid–base disturbance is derived from the addition of fixed acids or bases, extracellular buffering by HCO3 will account for nearly half of the

total chemical buffering occurring in the body fluids, leaving about half for proteins and phosphates within cells.

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Acid–Base Balance I Renal Physiology

Fig E.2 ▶ Bicarbonate buffers.

1

H+

2

OH–

Tissue

H++ HCO3–

OH–+ CO2

CO2

H+ elevated pCO2

CO2 OH– elevated pCO2

+ H+

+ OH–

Normal

Alveolar contact time

pCO2 rises

CO2 Increased elimination

Normal

HCO3–

CO2

Constant

Constant Alveolar contact time

pCO2 constant pCO2 falls

CO2

pCO2 constant

Decreased elimination

Respiratory Regulation Changes in ventilation can cause or correct disturbances in the acid–base balance. Changes of CO2 excretion rapidly affect plasma pH.

Compensation for changes in pH ​ 1. Acidic or alkaline arterial pH is detected.

2. Signals from respiratory chemoreceptors change the rate of alveolar ventilation.

3. Resulting hyper- or hypoventilation changes arterial pCO2 to return arterial pH to normal.

E.2 Renal Regulation of Acid–Base Balance The respiratory system cannot by itself restore pH to normal. The body supply of HCO3– needs to be restored after chemical buffering, and the buffered acids or bases in the body fluids need to be eliminated.

The renal system performs these two tasks to finally restore acid–base balance. The kidneys regulate acid–base balance in three ways.

1. Conservation of filtered HCO3–

– More than 99.9% of filtered HCO3– is reabsorbed by renal tubules

– Prevents the development of acidosis due to loss of HCO3–

2. Replenishment of depleted HCO3– (formation of new HCO3–) 3. Excretion of excess H+

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E-34

Renal Physiology I Acid–Base Balance

Conservation of Bicarbonate Normal urine is almost totally free of HCO3–. Bicarbonate is reabsorbed in three locations in the

nephron:

1. Proximal tubules

– Eighty to 90% of the filtered load is reabsorbed

2. Loops of Henle

– Another 2% of the filtered load is reabsorbed

3. Distal tubules and collecting ducts

– Eight percent is reabsorbed

Reabsorption in the proximal tubule. ​Secreted H+ is combined with filtered HCO3– in tubular fluid.

This is catalysed by luminal carbonic anhydrase. The secreted H+ is consumed by reactions with HCO3–,

keeping H+ concentration in the tubular fluid low. The slightly higher pH favors more H+ secretion as well as preventing H+ reabsorption.

Reabsorption in the distal nephron. ​Some secreted H+ combines with HCO3– without the action of

luminal carbonic anhydrase. Further HCO3– reabsorption occurs.

Factors Influencing Reabsorption Filtered load of HCO3– ​can vary widely. The rate of HCO3– reabsorption increases proportional to the load. Increased concentration of HCO3– in the filtrate causes

1. Increased tubular fluid pH 2. Increased H+ secretion 3. Increased HCO3– reabsorption Extracellular fluid volume. A ​ n expansion of extracellular fluid (ECF) volume results in decreased Na+ reabsorption. This decreases Na+-coupled H+ secretion and so decreases HCO3– reabsorption.

Carbon dioxide concentration. ​High arterial pCO2 will increase the rate of HCO3– reabsorption. This

may be through the effects of pCO2 on HCO3– formation in blood. It also may act on the cellular produc-

tion and secretion of H+. The dependence of HCO3– reabsorption on pCO2 allows the kidneys to respond to acid–base disturbances originating from respiratory causes.

Ion concentrations. ​High concentrations of other extracellular ions reduce the rate of HCO3– reabsorption.

1. High plasma [Cl–] decreases HCO3– reabsorption.

2. High plasma [K+] decreases H+ secretion and HCO3– reabsorption.

Hormones. H ​ CO3– reabsorption is affected by cer-

tain hormones:

1. Corticosteroids, aldosterone, and angiotensin II enhance HCO3– reabsorption.

Factor

Effect of increased concentration

HCO3–load Corticosteroids/ aldosterone/ angiotensin II

Increased reabsorption

Volume of ECF

2. Parathyroid hormone decreases HCO3 reab–

sorption.

Table E.2 outlines the factors influencing the reabsorption of bicarbonate (HCO3–).

Table E.2 ▶ Factors Influencing Reabsorption of Bicarbonate

Concentration of CO2 Concentration of Cl– Concentration of K+ Parathyroid

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Decreased reabsorption

Acid–Base Balance I Renal Physiology

E-35

Replenishment of Bicarbonate Hydrogen ions are produced within renal cells from carbonic acid with carbonic anhydrase and secreted into tubular fluid. H+ remains in tubular fluid as part of the buffer pairs and later is excreted. HCO3– is

formed within renal cells at the same time. HCO3– is transported across the basolateral membrane by a Cl––HCO3– exchanger. One new moiety of HCO3– is formed within renal cells for every H+ that is secreted

and excreted with non-HCO3– buffers. This “new” HCO3– is added to body fluids.

Titratable acid ​is urinary phosphate buffer that combines with secreted H+ (i.e., H2PO4–). It can be measured as the amount of strong base required to titrate 1 mL of urine back to the pH of the glomerular

filtrate or plasma. The amount of titratable acid formed is limited by the supply of urinary phosphate buffer.

– Seventy-five percent of filtered phosphate (HPO42–) is reabsorbed – Twenty-five percent of a low plasma phosphate is left to buffer

Ammonia Buffer System The NH3/NH4+ buffer system has a pK of 9.2. It is a relatively poor buffer in the pH range found in tubular fluid (pK is far from 7.4), but there is a plentiful supply of NH3 from renal cells.

NH3 ​is produced within proximal tubule cells by transamination reactions of glutamine. Medullary NH3 is uncharged and lipid soluble. It freely diffuses across cell membranes down its concentration gradient. In the lumen of the collecting duct, NH3 combines with secreted H+ to form NH4+.

Ammonium ion (NH4+) ​is charged and relatively impermeable. NH4 is “trapped” in the tubular fluid

and excreted in urine in the form of neutral salts (NH4)2SO4 or NH4Cl. This transport process is called diffusion trapping or nonionic diffusion.

Effectiveness. ​The effectiveness of the NH3 buffer system is enhanced during an acid load. The rate of synthesis of NH3 is regulated according to the acid–base status of the person. More NH3 is synthesized

during acidosis, permitting more excretion of excess acid. Under normal conditions all filtered HCO3– is reabsorbed, and an additional 40 to 60 mmoles of acid is secreted. This contributes 40 to 60 mmoles of

new HCO3– to blood and replenishes the HCO3– used to buffer the acid produced from metabolism. The

secreted acid is excreted with HPO42– (25%) or NH3 (75%).

E.3 Acid–Base Disturbances Normal Values Table E.3 lists the normal values of factors that describe the acid–base status of extracellular fluid (ECF).

Abnormal values. ​W hen acid–base balance is disturbed, pH changes, and other normal values change

Table E.3 ▶ Normal Values of Variables that Describe the Acid–Base Status of Extracellular Fluid Factor

Normal value

also.

Arterial pH

– Acidosis is the state in which arterial pH is < 7.36

Concentration of HCO3

24 mM

pCO2

40 mm Hg

[HCO3–]/ pCO2 ratio

20:1

(> 10% < 7.40).

– Alkalosis is the state in which arterial pH is > 7.44 (> 10% > 7.40).

7.4 –

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Efficiency of Ammonia and Phosphate Ammonia is more effective than phosphate at buffering the secreted H+. A large amount of H+ can be excreted without urine pH dropping to a very low level.

Acid Secretion at Low pH H + secretion is a gradient­limited transport process. The distal nephron cannot transport H+ against a concentration gradient exceeding 1000:1.

This occurs when urine pH equals 4.4. The body cannot excrete any more excess H+ if the urine pH drops below 4.4.

E-36

Renal Physiology I Acid–Base Balance

Disturbances Respiratory disturbance changes H+ concentration by a primary change in pCO2 because pCO2 is regulated

by the rate of alveolar ventilation. Metabolic disturbance changes primarily the concentration of HCO3– due to the addition or loss of fixed acids or bases derived from metabolic processes.

There are four primary acid–base disturbances:

1.

2.

3.

4.

Hyperkalemia Hyperkalemia (elevated potassium levels) occurs during acidosis. K+ is taken up by tubular cells in exchange for H+ secretion via the H+–K+ adenosinetriphosphatase (ATPase) antiporter.

Respiratory acidosis Respiratory alkalosis Metabolic acidosis Metabolic alkalosis

Response to acidosis. ​During acidosis the kidneys compensate by excreting more acidic urine. They 1. Continue to completely reabsorb HCO3– 2. Increase excretion of titratable acid and NH4+ Response to alkalosis. ​During alkalosis cell pH rises, causing 1.

2.

3.

4.

5.

6.

Decreased driving force for H+ secretion Decreased HCO3– reabsorption Alkalinized urine

Decreased NH3 retention

Decreased acid excretion Increased HCO3– elimination

Quantitation of renal tubular acid secretion and excretion. ​ Total rate of H+ secretion = Rate of HCO3– reabsorption + rate of titratable acid excretion + rate of NH4+ excretion

Total rate of H+ excretion = Rate of titratable acid excretion + rate of NH4+ excretion = Total rate of new HCO3- being added to the blood

In most cases a primary disturbance of one origin is accompanied by a secondary or compensatory response of the opposite origin. The compensatory response shifts pH toward its normal value by allowing HCO3– to increase or decrease from its normal value.

Compensatory response. ​The efficiency of compensatory responses is indicated by how close arterial pH is brought back to 7.4.

– Metabolic disturbances are almost instantaneous – Primary respiratory disturbances require several days

Respiratory Acidosis and Alkalosis Respiratory acidosis (RAc) ​results from high pCO2. It is due to failure of the lungs to excrete CO2 ad-

equately (Fig E.3). This can happen with pulmonary disease or decreased alveolar ventilation secondary to drugs, such as morphine. It is characterized by

1.

2.

3.

4.

Increased carbonic acid Increased HCO3– concentration

Change in [HCO3–]/ pCO2 ratio to < 20:1 (change in pCO2 is greater) Fall in plasma pH

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Acid–Base Balance I Renal Physiology

Fig E.3 ▶ Respiratory acidosis.

Bicarbonate buffer

Nonbicarbonate buffer (NBB) NBB–

HCO3– CO2

NBB-H

8.0 7.5 7.0

8.0 7.5 7.0

normal: pH 7.4 Decreased pulmonary elimination of CO2 CO2

HCO3– + H+

CO2 + H2O

1 Buffering

H+

NBB– + H+

Buffering by NBB– only

Respiratory acidosis: pH

2HCO3– + 2NH4+

NBB-H

Urea

H2O

Liver

2 Renal compensation

CO2 H+ + OH–

Increased excretion NH4+

Kidney

H+

CO2 HCO3–

Increased pulmonary elimination of CO2

Increased production (kidney) HCO3– and sparing (liver)

HCO3– HCO3– + H+

Renal compensation of acidosis is achieved: pH

® CO2 + H2O

NBB is regenerated

But: [HCO3–]act and pCO2 are increased

Renal compensation ​for the increased pCO2 involves 1.

2.

3.

4.

Increased H+ production and secretion from renal tubular cells Increased HCO3– reabsorption Increased H+ excretion

Production of “new” HCO3–

These compensations return the [HCO3–]/ pCO2 ratio closer to 20:1.

Ion concentration changes ​ 1. Plasma [Cl–] decreases 2. Plasma [K+] increases

– Kidney secretes more H+ as compensation

– Kidney reabsorbs more K+ with operation of the H+–K+ ATPase antiport protein

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Renal Physiology I Acid–Base Balance

Compensated respiratory acidosis (cRAc) ​is indicated by 1. Near normal pH 2. Still some elevation in pCO2 3. Increased plasma HCO3– Respiratory alkalosis (RAk) ​results from low pCO2 due to excessive loss of CO2 (e.g., hyperventilation). RAk

1. Decreases HCO3– concentration 2. Raises the [HCO3–]/ pCO2 ratio to > 20:1 3. Raises the pH Renal compensation ​involves 1.

2.

3.

4.

5.

Decreased CO2 within renal cells

Decreased reabsorption of HCO3–

Decreased H+ secretion into the tubules Increased excretion of HCO3–

Further decreased plasma [HCO3–]

Compensations return the [HCO3–]/ pCO2 ratio nearer to 20:1.

Compensated respiratory alkalosis (cRAk) ​is indicated by 1. Near normal pH 2. Still-depleted HCO3– store

Metabolic Acidosis and Alkalosis Metabolic acidosis (MAc) ​results from abnormal retention of fixed metabolic acids (e.g., diabetes) (Fig E.4). It is characterized by

1. Decreased HCO3– concentration 2. Decreased [HCO3–]/ pCO2 ratio to < 20:1 3. Decreased pH Respiratory compensation ​causes 1. Stimulation of the respiratory center to eliminate more CO2 2. Reduction in H2CO3– concentration Renal compensation ​also occurs unless acidosis is due to renal failure. It results in 1. Virtually complete reabsorption of HCO3– 2. Increase in plasma [Cl–], because more Na+ is absorbed with Cl– than with HCO3– 3. Increased excretion of titratable acid and NH4+ An acute episode can be partly compensated by increased HCO3– production.

Compensated metabolic acidosis (cMAc) ​is indicated by 1. pH closer to 7.4 but not quite normal 2. [HCO3–]/ pCO2 ratio returns to 20:1 3. Further decrease in HCO3–

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Acid–Base Balance I Renal Physiology

Fig E.4 ▶ Metabolic acidosis.

Bicarbonate buffer

Nonbicarbonate buffer (NBB)

HCO3–

NBB– CO2

NBB-H

8.0 7.4 7.0

7.4

Normal: pH 7.4 Addition of H+ H+

H+

CO2

1 Buffering HCO3– +

+

H

–

® CO2 + H2O

+

NBB + H

Buffering by HCO3–

® NBB–H

Buffering by NBB–

Non-respiratory (metabolic) acidosis: pH Stimulation of chemosensors Total ventilation increases Increased pulmonary CO 2 elimination of CO2

2 Respiratory compensation

a

pH rises

b +

H

c

CO2

Additional HCO3– consumption HCO3– +

NBB– is regenerated +

H

® CO2 + H2O

Respiratory compensation of acidosis is achieved: pH But: [HCO3–]act and pCO2 are decreased

Increased renal excretion of H+ and NH4+

HCO3– replenished

Metabolic alkalosis (MAk) ​results from 1. Excessive loss of H+ (e.g., loss of HCl from vomiting) 2. Excessive intake or retention of bases (e.g., NaHCO3, lactate) It is characterized by an

1. Increase in

– HCO3– concentration

– [HCO3–]/ pCO2 ratio > 20:1

– pH

– Intracellular [K+]

2. Decrease in

– Plasma [Cl–]

– Plasma [K+] due to the H+–K+ ATPase transporter

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Renal Physiology I Acid–Base Balance

Respiratory compensation ​causes 1. Retention of CO2 2. Increased H2CO3 concentration Renal compensation involves increased renal excretion of HCO3–. Paradoxical aciduria may occur; when all filtered HCO3– is reabsorbed, any further H+ secretion lowers pH. The effectiveness of respiratory com-

pensation is limited. Retention of CO2 will tend to increase H+ secretion and HCO3– reabsorption. These are the reverse effects of renal compensation.

Compensated metabolic alkalosis (cMAk) ​is indicated by 1. pH closer to 7.4 but not quite normal 2. [HCO3–]/ pCO2 ratio returns to 20:1 3. Further increase in plasma HCO3–

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