The Kidneys and Regulation of Water and Inorganic Ions

Functions of the Kidneys

I. Regulation of water, inorganic ion balance, and acid–base balance (in cooperation with the lungs; Chapter 13) II. Removal of metabolic waste products from the blood and their excretion in the urine III. Removal of foreign chemicals from the blood and their excretion in the urine IV. Gluconeogenesis V. Production of hormones/enzymes: A. Erythropoietin, which controls erythrocyte production (Chapter 12) B. Renin, an enzyme that controls the formation of angiotensin, which influences blood pressure and sodium balance (this chapter) C. Conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, which influences calcium balance (Chapter 11)

Kidneys

(1) regulate the water and ionic composition of the body, (2) excrete waste products, (3) excrete foreign chemicals, (4) produce glucose during prolonged fasting, and (5) release factors and hormones into the blood (renin, 1,25-dihydroxyvitamin D, and erythropoietin)

renal functions (1)–(3) are accomplished by _____

continuous processing of the plasma

renal function (2)—excretion of metabolic waste products; examples

urea (from protein), uric acid (from nucleic acid), and creatinine (from muscle creatine)

urine flow

kidneys → ureters → bladder → urethra → environment

blood flow

aorta → renal arteries → renal circulation (details below) → renal veins

calyx (funnel-shaped) →

→ renal pelvis → ureters

Nephron

functional unit of the kidneys (approximately 1 million per kidney)

Nephrons consist of _____

a renal corpuscle and a renal tubule

Renal corpuscle is composed of _____

a capillary tuft (glomerulus) and a Bowman’s capsule into which the tuft protrudes. Within Bowman’s capsule is Bowman’s space, from which fluid flows into the start of the nephron tubule.

Fluid flow

tubule extends from Bowman’s capsule and is subdivided into the proximal tubule, loop of Henle (descending and ascending limbs), distal convoluted tubule, collecting ducts (cortical and medullary)

Multiple collecting ducts join and empty into the _____, from which urine flows through the _____ to the _____.

renal pelvis; ureters; bladder

Each glomerulus is supplied with blood by an _____ and drained by an _____ (which leaves the glomerulus to branch into _____, which supply the tubule).

afferent arteriole; efferent arteriole; peritubular capillaries

Vasa recta

long capillary loop that runs next to the loop of Henle

hairpin-loop blood vessels that prevent the countercurrent gradient (created by the long loops of Henle) from being washed away

Filtration barrier in the renal corpuscle: consists of three layers…

capillary endothelium, basement membrane, Bowman’s capsule epithelium (podocytes); mesangial cells represent third cell type

juxtamedullary

renal corpuscle located in cortex just next to the medulla, long loops of Henle dive deep into medulla

cortical

~ 85% of all nephrons; short loops of Henle

Juxtaglomerular apparatus 

composed of the macula densa (patch of tubular wall cells at end of ascending limb of the loop of Henle) and juxtaglomerular (JG cells) (afferent arteriole wall cells that secrete renin)

Three basic renal processes:

glomerular filtration, tubular reabsorption, and tubular secretion

Urine formation begins with _____ — approximately 180 L/day—of essentially protein-free plasma into Bowman’s space

glomerular filtration

Glomerular filtrate

contains all plasma substances other than proteins (and substances bound to proteins) in virtually the same concentrations as in plasma

Glomerular filtration (_____) is driven by the hydrostatic pressure in the glomerular capillaries and is opposed by both the _____ in Bowman’s space and the _____ due to the proteins in the glomerular capillary plasma.

net glomerular filtration pressure; hydrostatic pressure; osmotic force

Glomerular filtration rate (GFR)

determined by net filtration pressure, the permeability of the corpuscular membranes, and the filtration surface area

filtered load

GFR × plasma concentration of filtered substance

Filtrate movement through the tubules

Certain substances are reabsorbed either by diffusion or by mediated transport.

Substances to which the tubular epithelium is permeable are reabsorbed by diffusion because _____

water reabsorption creates tubule-interstitial-fluid-concentration gradients.

Active reabsorption of a substance requires the participation of _____ in the _____ (between tubular lumen and cell) or _____ (between interstitial space next to capillaries and cell).

transporters; apical membrane; basolateral membrane

tubular reabsorption rates

high for nutrients, ions, and water; lower for waste products

tubular secretion

movement of a substance from peritubular capillary plasma into the tubule

Transport maximum

is exhibited by substances moved by mediated transporters. If the filtered load of a substance exceeds the reabsorptive transport maximum, the substance will be excreted in the urine.

Example: poorly controlled diabetes mellitus (hyperglycemia). Filtered load of glucose exceeds reabsorptive transport maximum so glucose “spills” into the urine, which can lead to decrease in renal function (diabetic nephropathy). ∙ Another example: defect in glucose transporter (familial renal glucosuria)

Clearance

volume of the plasma completely cleared of a substance per unit time (e.g., units are in mL/min)

Clearance is calculated by

dividing the mass of the substance excreted per unit time by the plasma concentration of the substance

Glucose clearance

Since it is important not to lose glucose in the urine, it is completely reabsorbed so its renal clearance rate is zero in healthy people

Inulin

small carbohydrate that is filtered but not reabsorbed or secreted; infused experimentally; clearance rate equals GFR

Creatinine clearance

estimates GFR clinically because it is filtered, not reabsorbed, and secreted only a little

Renal plasma flow

is estimated by the clearance of a substance (e.g., infused para-aminohippurate [PAH]) that is filtered, not reabsorbed, and 100% secreted. All that enters the kidneys from the blood is cleared.

Spinal micturition reflex

involuntary ∙ Bladder distension stimulates stretch receptors that trigger spinal reflexes. ∙ These reflexes lead to contraction of the detrusor muscle (bladder smooth muscle). ∙ mediated by parasympathetic and sympathetic neurons ∙ mediated by relaxation of both the internal and the external urethral sphincters (inhibition of neural input)

Voluntary control

mediated by motor nerves supplying the external urethral sphincter

Incontinence

involuntary release of urine that occurs most commonly in elderly people (particularly women)

∙ Stress incontinence: due to sneezing, coughing, or exercise ∙ Urge incontinence: associated with desire to urinate

Water balance

∙ gain water via ingestion and internal production

∙ lose water via urine, the gastrointestinal tract, evaporation from the skin and respiratory tract (insensible water loss), and sweat

Na+ and Cl− balance

gains by ingestion; losses via the skin (in sweat), the gastrointestinal tract, and urine

Homeostasis for both water and Na+

Renal excretion is the major control point for maintaining stable balance.

Renal Na+ handling

filtration (glomerulus) and reabsorption (primary active process dependent upon Na+/K+-ATPase pumps in the basolateral membranes of the tubular epithelium); Na+ not secreted

Na+ entry into tubular epithelial cells from the tubular lumen is passive. Depending on the tubular segment, it is either through ion channels or by cotransport or countertransport with other substances.

Ascending limb of loop of Henle

reabsorption of NaCl (not water) via Na-K-2Cl cotransporters (NKCC)

Na+ reabsorption

creates an osmotic difference across the tubule (drives water reabsorption through water channels [aquaporins] and where permeable, through the paracellular path)

Vasopressin (antidiuretic hormone)

does not exert major direct effects before the collecting-duct system

Collecting-duct system

Vasopressin increases water permeability (low vasopressin leads to production of large volume of dilute urine—nonosmotic diuresis).

Diabetes insipidus

excess loss of dilute urine, due to low vasopressin (central diabetes insipidus) or renal insensitivity to vasopressin (nephrogenic diabetes insipidus)

Osmotic diuresis

water loss in the urine due to excessive solute excretion (e.g., glucosuria in diabetes mellitus)

Obligatory water loss

minimal volume of water loss (~ 0.44 L/day)

Ascending loop of Henle

active transport of sodium chloride results in increased osmolarity of the interstitial fluid of the medulla but a dilution of the luminal fluid

Vasopressin increases the permeability of the _____ to water by increasing the number of AQP2 water channels inserted into the apical membrane. Water is reabsorbed by this segment until the luminal fluid is isosmotic to plasma in the cortical peritubular capillaries

cortical collecting ducts

Luminal fluid enters and flows through the _____; the concentrated medullary interstitial fluid causes water to move out of these ducts, made highly permeable to water by vasopressin. The result is concentration of the collecting-duct fluid and the urine.

medullary collecting ducts

Urea recycling

helps establish a hypertonic medullary interstitial fluid

Na+ excretion

difference between the amount of Na+ filtered and reabsorbed

Filtered load of Na+

determined by GFR (and plasma concentration of Na+ ) ∙ also controlled by baroreceptor reflexes via sympathetic outflow to the renal arterioles (minor effect)

Tubular Na+ reabsorption

adrenocortical hormone aldosterone stimulates Na+ reabsorption in the cortical collecting ducts

Renin–angiotensin system (RAS)

major controller of aldosterone secretion

decreases in extracellular volume lead to increased renin secretion by three inputs

1.  stimulation of the renal sympathetic nerves to the juxtaglomerular cells by extrarenal baroreceptor reflexes

2.  pressure decrease sensed by the juxtaglomerular cells (intrarenal baroreceptors)

3.  signal from low Na+ or Cl− concentration in the lumen of the macula densa

Renin catalyzes conversion of _____

angiotensinogen → angiotensin I

_____ catalyzes conversion of angiotensin I to angiotensin II, which in turn causes vasoconstriction and stimulation of aldosterone secretion

Angiotensin-converting enzyme (ACE)

RAS drugs

ACE inhibitors (e.g., lisinopril), angiotensin II receptor antagonists (e.g., losartan), aldosterone receptor antagonists (e.g., epleronone)

Atrial natriuretic peptide

secreted by cells in the atria in response to cardiac atrial distension ∙ inhibits Na+ reabsorption and aldosterone secretion; also increases GFR

Pressure natriuresis

Arterial pressure acts locally (directly) on the renal tubules; increased pressure causes decreased Na+ reabsorption (increases excretion).

Water excretion

difference between the amount of water filtered and the amount reabsorbed ∙ Major control is via vasopressin-mediated control of water reabsorption (control of GFR makes a minor contribution).

Vasopressin secretion

by the posterior pituitary

Osmoreceptors (located in hypothalamus)

High body fluid osmolarity stimulates vasopressin secretion and a low osmolarity inhibits it.

Extracellular fluid volume

Low volume stimulates vasopressin secretion via the baroreceptor reflexes; high volume inhibits vasopressin secretion.

Other stimuli to vasopressin secretion

Examples are nausea, hypoxia, pain, and fear

Severe sweating can lead to a decrease in plasma volume and an increase in plasma osmolarity. ∙ GFR decreased and aldosterone increased (via the RAS); together decrease Na+ excretion ∙ increases vasopressin, which decreases H2O excretion ■ Net result: Renal retention of Na+ and H2O acts to minimize hypovolemia and maintain plasma osmolarity.

Thirst

stimulated by a variety of inputs (baroreceptors, osmoreceptors, and possibly angiotensin II)

Salt appetite

not of major regulatory importance in humans

Potassium balance

Homeostasis is achieved when the amount of K+ in the urine equals the amount ingested minus the amounts lost in feces and sweat

Hyperkalemia and hypokalemia

increased and decreased plasma K+ , respectively

K+ is freely filterable at the renal corpuscle and undergoes both reabsorption and secretion. ∙ secretion

occurs in cortical collecting ducts; is the major controlled variable determining K+ excretion

Increase in body K+

extracellular K+ increases above normal resulting in: ∙ the cortical collecting ducts to increase K+ secretion ∙ direct stimulation of aldosterone secretion from the adrenal cortex, which leads to an increase in renal K+ secretion

Ionized plasma calcium and phosphate

filtered in the glomerulus ∙ About half of the plasma calcium and phosphate is filtered. ∙ The half that is not filtered is bound to plasma protein or complexed with other plasma ions.

Parathyroid hormone (PTH)

secreted from the parathyroid glands in response to a decrease in plasma calcium or an increase in plasma phosphate ∙ increases calcium ion absorption in the distal convoluted tubule and early cortical collecting duct ∙ decreases phosphate ion reabsorption in the proximal tubule

Each _____ of the nephron is responsible for a different function.

segment

Proximal tubules

responsible for the bulk reabsorption of solute and water

Loops of Henle

generate the medullary osmotic gradient; allow for the passive reabsorption of water in the collecting ducts

Distal tubules and collecting ducts

most regulation (fine-tuning) of the excretion of solutes and water

Diuretics

increase urine volume. ∙ Most act by inhibiting the reabsorption of Na+ and water.

Classes of diuretics

act on different nephron segments

Loop diuretics (e.g., furosemide)

inhibit NKCC (increase Na+ and water excretion) in ascending limb of loop of Henle

Potassium-sparing diuretics

inhibit Na+ reabsorption in the cortical collecting ducts (do not increase K+ secretion).

Potassium-sparing diuretics either block _____

aldosterone action (spironolactone or epleronone) or Na+ channels (triamterene or amiloride).

Osmotic diuretics (e.g., mannitol)

are filtered but not reabsorbed; they retain water in urine.

Acidosis and alkalosis

high plasma H+ concentration (low pH) and low plasma H+ concentration (high pH), respectively

Total-body balance of H+

metabolic production (CO2 and nonvolatile acids) and net gains or losses via the respiratory system, gastrointestinal tract, and urine

stable balance of H+ achieved by

regulation of urinary losses

Buffers

minimize changes in H+ concentration Buffer + H+ HBuffer ∙ reversibly combine with H+ (e.g., with HCO3 − and intracellular proteins)

major extracellular buffering system is

the CO2/HCO3 − system

major intracellular buffers are

proteins and phosphates

Kidneys and the respiratory system

homeostatic regulators of plasma H+ concentration ∙ Kidneys achieve total body H+ balance

Metabolic alkalosis

decrease in arterial plasma H+ concentration ∙ causes reflexive decrease in breathing relative to metabolic rate (hypoventilation) → increases arterial PCO2 → increases plasma H+ concentration toward normal

Metabolic acidosis

increase in plasma H+ concentration ∙ causes reflexive increase in breathing relative to metabolic rate (hyperventilation) → decreases arterial PCO2 → decreases H+ concentration toward normal

The kidneys maintain a stable plasma H+ concentration primarily by

regulating plasma HCO3 − concentration.

excrete HCO3 − in the urine or add new HCO3 − to the blood

Filtered HCO3-

reabsorbed when H+ (generated in the tubular cells by carbonic anhydrase catalysis) is secreted into the tubular lumen and combines with filtered HCO3 − ; secreted H+ not excreted in this situation

Filtered phosphate ion (or other nonbicarbonate buffers)

∙ Secreted H+ combines in the tubular lumen with nonbicarbonate buffers and is excreted. ∙ New HCO3 − is contributed to the blood.

Ammonium excretion

produced from glutamate and contains H+ ∙ New HCO3 − is contributed to the blood.