Renal Physiology and Regulation of Water and Inorganic Ions

Photo: Glomerulus in a human kidney scanning electron micrograph. From: Widmaier EP, Raff H & Strang KT. Vander’s Human Physiology:
The Mechanisms Of Body Function, 13th Ed. New York, NY: McGraw-Hill Companies, Inc., 2014: 490

Marc Imhotep Cray, M.D.
Physiological Basis of
Renal Pharmacology:
A Rapid Review
2

Interdigitation of Renal system with
Cardiovascular and Endocrine systems
3
 Heart is principal source of atrial natriuretic peptide (ANP) acts in classic
endocrine fashion to induce natriuresis at a distant target organ (kidney)
 Erythropoietin, a traditional circulating hormone, is made in kidney and
stimulates erythropoiesis in bone marrow
Kidney is also integrally involved in renin-angiotensin-aldosterone axis and is a
primary target of several hormones, including parathyroid hormone (PTH),
mineralocorticoids, and vasopressin
 Hormones play an important role in maintenance of blood pressure, intravascular
volume, and peripheral resistance in cardiovascular system
 Vasoactive substances such as catecholamines, angiotensin II, endothelin, and nitric
oxide are involved in dynamic changes of vascular tone in addition to their multiple
roles in other tissues

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Overview of Renal Pharmacology
5
 For many drugs, kidney is major organ of elimination
 In healthy human, kidney receives between 20% and 25% of blood
pumped by each beat of heart
 Kidney’s primary function is 2-fold:
1. to eliminate unwanted substances (eg, toxic substances, drugs, and
their metabolites) and
2. to retain (reabsorb, recycle) wanted materials (eg, water and
electrolytes)
 Amount of drug and metabolites eliminated (cleared) from body depends
on several factors, including
 glomerular filtration rate (GFR)
 urine flow rate and
 pH

Overview (2)
6
 Rate of renal elimination is net result of glomerular filtration, secretion,
and reabsorption
 Functional microscopic unit of kidney is nephron a tube that is open at
one end and closed at other end by a selectively permeable membrane
 Nephron has 5 distinct anatomical and functional units:
1. glomerulus
2. proximal convoluted tubule
3. loop of Henle
4. distal convoluted tubule
5. collecting duct
 Large drug molecules (>5-6 kd) and drug molecules that are bound to
plasma proteins do not pass into nephron of a healthy kidney

Overview (3)
7
 Most of water and other substances that enter nephron are reabsorbed
into surrounding tissue and blood supply
 The small residual amount is excreted as urine
 Flow and contents of urine are determined by 3 processes, most of
which are coupled:
1. filtration through glomerulus
2. reabsorption of water and other substances from tubule, and
3. secretion of substances into tubule
 Processes involve
 active transport
 passive transport, or
 osmotic gradients

Overview (4)
8
Most of water and solutes (eg, sodium, glucose, bicarbonate,
amino acids) are reabsorbed during passage through proximal
convoluted tubule (PCT)
 Further concentration occurs in countercurrent system of loop of Henle
Thick ascending limb and distal convoluted tubule (DCT) are
involved in Na+-K+ and H+ exchange under tight homeostatic
control and hormonal influence, including adrenal steroid
hormones such as aldosterone
Collecting duct is primary site of action of antidiuretic hormone
(ADH)

Overview (5)
9
Each class of diuretics affects different processes located at
different sites along nephrons
 Therefore, each class has its own set of associated therapeutic
advantages or drawbacks
 Each also has characteristic effects on electrolyte balance an
important consideration for long-term use
 Many effects can be anticipated on basis of a drug’s mechanism of
diuretic action and can be ameliorated by dietary or drug regimens
 Combinations of diuretics may offer a remedy for resistance to a single
agent
 A decline in renal function, whether caused by advanced age or disease,
has a significant effect on clearance of drugs that are eliminated
predominantly via the kidney
 Dosages must be adjusted in these situations

Organization and Functions of
Renal System
10

Gross Anatomy
11
 Kidneys are a pair of specialized,
retroperitoneal organs located at
level between lower thoracic and
upper lumbar vertebrae
 Each kidney is reddish brown and has
a characteristic shape:
 a convex lateral edge and
concave medial border with a
marked depression or notch
termed hilus
 Each adult kidney is approx. 11 cm
long, 2.5 cm thick, and 5 cm wide
and weighs 120 to 170 g
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated
Pharmacology, Updated Edition. Saunders, 2014
Anterior surface of right kidney

Gross Anatomy (2)
12
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated
Pharmacology, Updated Edition. Saunders, 2014
Seeley R. et.al. Seeley’s Anatomy & Physiology 10th ed.
New York, NY: McGraw-Hill , 2010.

13
Normal Kidney, gross
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Functional Anatomy
14
 Kidneys contribute to several important processes, including
 regulation of fluid volume
 regulation of electrolyte and acid-base balance
 excretion of metabolic wastes and
 elimination of toxic compounds, drugs, and their metabolites
 Kidney also acts as an endocrine organ
 Each kidney is divided into a cortex and a medulla, both parts containing
nephrons (approx. 1.25 million per kidney)
Fluid that exits a nephron flows out papilla of a pyramid (8-15 per medulla),
enters a minor calyx, joins effluent of other minor calyces in major calyx, and
is eliminated as urine through ureter

Functions of Kidneys
15
Kidneys perform a host of functions (5), including:
1. Regulation of fluid and electrolyte balance:
 kidneys regulate volume of extracellular fluid (ECF)
through reabsorption and excretion of NaCl and water
They are also site of regulation of plasma levels of other
key substances (Na+, K+, Cl−, HCO3−, H+, Ca2+, and
phosphates)

Key renal processes involved in regulation of
circulating substances: fluid and electrolyte balance
16
Filtration of fluid and solutes from plasma into nephrons
Reabsorption of fluid and solutes from renal tubules into peritubular
capillaries
Secretion of select substances from peritubular capillaries into tubular
fluid, which facilitates their excretion
 both endogenous (e.g., K+, H+, creatinine, norepinephrine, and dopamine) and
exogenous (e.g., para-aminohippurate [PAH], salicylic acid, and penicillin) substances
can be secreted into tubular fluid and subsequently excreted in urine
Excretion of excess fluid, electrolytes, and other substances (e.g., urea,
bilirubin, and acid [H+])

Functions of Kidneys cont.
17
2. Regulation of plasma osmolarity:
 “Opening” and “closing” of specific water channels (aquaporins) in
renal collecting ducts produces concentrated and dilute urine
(respectively) allowing regulation of plasma osmolarity and ECF
volume
3. Elimination of metabolic waste products:
 Urea (from protein metabolism)
 Creatinine (from muscle metabolism)
 Bilirubin (from breakdown of hemoglobin)
 Uric acid (from breakdown of nucleic acids)
 Metabolic acids, and foreign substances such as drugs are excreted
in urine

18
4. Production/conversion of hormones:
 kidney produces erythropoietin and renin
 Erythropoietin stimulates red blood cell production in bone
marrow
 Renin, a proteolytic enzyme, is secreted into blood and converts
angiotensinogen to angiotensin I which is then converted to
angiotensin II by angiotensin-converting enzyme (ACE) in lungs
and other tissues
o renin-angiotensin system is critical for fluid-electrolyte
homeostasis and long-term blood pressure regulation
 Renal tubules also convert 25-hydroxyvitamin D to active 1,25-
dihydroxyvitamin D, which can act on kidney, intestine, and
bone to regulate calcium homeostasis

19
5. Metabolism:
 Renal production of ammonia through ammoniagenesis has an
important role in acid-base homeostasis
 Kidney, like the liver, has ability to produce glucose through
gluconeogenesis

Microscopic Anatomy: The Nephron
20
 Each kidney contains approximately 1 to 2.5 million tubular
nephrons (Greek nephros, meaning kidney)
 A nephron originates in glomerular apparatus
 part adjoining this corpuscle is termed proximal convoluted
tubule because of its tortuous course that remains close to its
point of origin
 Tubule then straightens in direction of center of kidney and
forms Henle loop, by making a hairpin turn and returning to
vascular pole of its parent renal corpuscle

Nephron (2)
21
 The Henle loop extends to distal convoluted tubule and then to
collecting tubule
 Collecting tubules unite to form larger collecting ducts
 Most nephrons originate in kidney cortex, are short, and extend only to
outer medullary zone
 Other nephrons originate close to medullary level (juxtamedullary
glomeruli) and extend deep into medulla, almost as far as the papilla
 Each part of nephron acts in physiologic processes that affect or are
affected by metabolism of drug molecules (or their metabolites)

Marc Imhotep Cray, M.D. 22
Widmaier EP, Raff H & Strang KT Vander’s Human Physiology: The Mechanisms Of Body Function, 13th Ed. McGraw-Hill, 2014.

23
Renal blood flow
Glomerular filtration rate
Urine flow rate
1-1.2 L/min
100-125 mL/min
140-180 L/d
0.5-18 L/d
Number of nephrons
Cortical
Juxtamedullary
2.5 million
2.1 million
0.4 million
Nephron (3)
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Blood Vessels Surrounding Nephrons
24
 Critical to multiple kidney functions is close association of nephrons
with blood vessels water and other substances pass from nephron to
blood and vice versa
 Kidneys have a great influence on volume and composition of plasma
and urine, so architecture of renal vasculature reflects functions other
than tissue oxygenation
 In outer renal cortex, each afferent arteriole enters a glomerulus,
divides, forms a capillary network, becomes an efferent arteriole, and
exits glomerulus
Glomerulus (human);
H and E stain 3500X
P = Proximal tubule
D = Distal tubule
P = Juxtaglomerular cells

Blood Vessels Surrounding Nephrons (2)
25
Neurotransmitters, drugs, and environmental factors that relax
afferent arteriole or constrict efferent arteriole increase GFR
Contrastly;
Neurotransmitters, drugs, and environmental factors that
constrict afferent arteriole or relax efferent arteriole reduce GFR
Blood vessels surround and outnumber tubular segments of each
nephron and form a peritubular network of capillaries allows
exchange of water, electrolytes, and other substances
 This exchange is target for actions of many drugs, especially
diuretics

Pattern of Blood
Vessels in
Parenchyma of
Kidney: Schema
26
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Saunders, 2014

Microscopic Anatomy: The glomerulus
27
 Glomerulus is an important interface between afferent arteriolar
blood flow and nephron
 Glomerulus filters plasma, and fluid, minus cells, enters nephron as an
ultrafiltrate
 Glomerulus is also a barrier to molecules larger than approx. 5 kd (eg,
plasma proteins)
 Thus, plasma proteins and drug molecules bound to them do not
pass into nephrons of a healthy kidney only smaller free drug or
metabolite molecules do so
o However, damaged glomeruli allow passage of plasma proteins,
and presence of these proteins in urine indicates a renal
disorder

Glomerulus (2)
28
 In renal disease, drugs enter nephron and are excreted at a rate greater
than normal, which is noted as a shorter plasma half-life of drugs (or
metabolites) subtherapeutic levels
 renal disease also cause reduced elimination of drugs normally
excreted via the kidney longer plasma half-life of drugs (or
metabolites) toxicity
 Hormones and hormone-mimetic drugs that alter GFR include
 angiotensin II (AT-II) (constricts afferent arterioles and thereby
reduces GFR)
 atrial natriuretic peptide (ANP) (dilate afferent arterioles and thus
increase GFR)
 prostaglandin E2 (dilate afferent arterioles and thus increase GFR)

Histology of
Renal Corpuscle
29
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology,
Updated Edition. Saunders, 2014
Le T and Bhushan V. First Aid for the USMLE Step 1 2015 .
McGraw-Hill 2015.

30
Diagram of renal corpuscle structure:
A – Renal corpuscle
B – Proximal tubule
C – Distal convoluted tubule
D – Juxtaglomerular apparatus
1. Basement membrane (Basal lamina)
2. Bowman's capsule – parietal layer
3. Bowman's capsule – visceral layer
3a. Pedicels (Foot processes from podocytes)
3b. Podocyte
4. Bowman's space (urinary space)
5a. Mesangium – Intraglomerular cell
5b. Mesangium – Extraglomerular cell
6. Granular cells (Juxtaglomerular cells)
7. Macula densa
8. Myocytes (smooth muscle)
9. Afferent arteriole
10. Glomerulus Capillaries
11. Efferent arteriole https://en.wikipedia.org/wiki/Renal_corpuscle#/media/File:Renal_corpuscle.svg

Normal Kidney, microscopic
Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Microscopic Anatomy: Tubular Segments
32
 Structure and function of tubular segments are important for
understanding drug effects on kidney
 Proximal portion and thick segment of descending limb have a similar
structure (slight variation in cell size and shape)
 Tight junctions between cells prevent escape of material in tubular lumen
 Proximal segment cells act to reabsorb water and other substances
 Proximal segment’s brush border is replaced in thin tubular segment by
fewer short microvilli
 Permeability to water and position of descending and ascending limbs of
Henle loop create a countercurrent multiplier for urine concentration

Tubular Segments (2)
33
Distal segment of nephron consists of thick ascending limb of
Henle loop and distal convoluted tubule
The ultrastructure and large surface area of distal segment
 serve energy requirements of active Na+ transport from
luminal fluid
 formation of ammonia, and
 urine acidification
Drug action in each segment alters kidney function in specific
ways

Marc Imhotep Cray, M.D. 34
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology,
Updated Edition. Saunders, 2014
Tubular Segments (3)

Ion and Water Reabsorption
35
More than 99% of glomerular ultrafiltrate is reabsorbed from
tubular lumen kidney is thus more an organ of retention than
of elimination
Driving factor for water and Na+ reabsorption in nephron is
active Na+ transport
Drugs affecting Na+ transport can alter urine flow and
composition
Na+ reabsorption occurs against conc. and electrical potential
gradients (lumen is electrically negative compared with
peritubular fluid) and is an active process requiring energy (ATP)

Ion and Water Reabsorption (2)
36
Active uptake mechanism (pump) for Na+ involves a
cotransporter that exchanges Na+ for K+, an important factor for
drugs that affect Na+ transport
Cl− and other ions move by cotransport with Na+ or other ions
or by passive diffusion
Osmotic gradient (established by ion transport) drives water out
of lumen
Hormones and drugs that decrease ion transport or osmotic
gradient reduce ion and water reabsorption and thus increase
urine flow (diuresis) and ion content

Bicarbonate Reabsorption
37
A notable ion with regard to drug metabolism is bicarbonate, or
HCO3 −
HCO3− and Cl− are most relevant ions for class of diuretic drugs
known as carbonic anhydrase inhibitors
 HCO3− is freely filtered through glomerulus and enters nephron
Almost all of it is reabsorbed along the tubule—most of it (80%–
85%) in proximal convoluted tubule—in a process that involves
H+ secretion, thus reabsorption of HCO3 − is inhibited by
carbonic anhydrase inhibitors

Bicarbonate Reabsorption (2)
38
Although usually all filtered HCO3− is reabsorbed and none
is excreted in urine, a number of factors influence H+
secretion by nephron, and a small amount of HCO3− can be
lost in urine
Kidneys generate new HCO3 − to replenish this loss
 Acetazolamide is a diuretic that affects HCO3− exchange,
predominantly at proximal convoluted tubule (more on this
in diuretics subsection)

Potassium Excretion
39
 Kidneys are primary route of excretion of K+ from body
 Although a large fraction of filtered K+ is reabsorbed along proximal
convoluted tubule and loop of Henle, amount of K+ excretion in urine is
determined mainly by highly variable secretory activity of distal
convoluted tubule
 Several diuretics and other drugs cause excess urinary K+ loss as a side
effect
 by increasing distal tubular flow rate and Na+ delivery (eg, ethacrynic acid and
furosemide)
 by alkalinizing distal tubular fluid (eg, carbonic anhydrase inhibitors such as
acetazolamide), or
 by blocking tubular K+ reabsorption (eg, ouabain)
 Some diuretics, known as potassium-sparing diuretics, do not cause K+
loss

Renal Physiology: Fluid compartments
 “HIKIN”: HIgh K+ INtracellularly
60–40–20 rule (% of body weight for
average person):
 60% total body water
 40% ICF
 20% ECF
 Plasma volume can be measured by
radiolabeling albumin
 Extracellular volume can be
measured by inulin or mannitol
 Osmolality = 285–295 mOsm/kg H2O
Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-
Hill Education, 2016.

Practical Application: Measuring
Glomerular Filtration Rate (GFR)
41
GFR is an important characteristic of normal kidney functioning
and an important variable in elimination of drugs and their
metabolites
 In general, greater GFR is, greater rate of elimination is
GFR can be measured noninvasively by determining rate at
which a substance is removed from plasma (or appears in
urine) requires use of a substance that is freely filtered by
glomerulus and is neither reabsorbed nor secreted within
nephron
 These criteria are fulfilled by the 5-kd fructose
polysaccharide inulin

Measuring GFR (2)
42
For the assay, after a uniform blood level of inulin is established,
measurement of concentration of inulin in plasma (Pin),
concentration of inulin in urine (Uin), and urine flow rate (V)
yields the GFR from equation: GFR = (V × Uin)/Pin
GFR of a healthy adult kidney is approximately 120 mL/min
Decreased clearance, which is common in elderly, usually
results in slower drug elimination and requires an appropriate
dosage adjustment Note: Creatinine clearance is an
approximate measure of GFR. Slightly
overestimates GFR because creatinine is
moderately secreted by renal tubules.

Marc Imhotep Cray, M.D. 43Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014
Measuring GFR (3)

Renal Clearance Principle
44
 “Clearance” describes volume of plasma that is cleared of a substance
per unit time
 Renal clearance (C) of a substance provides information on how kidney
handles that substance
 Because inulin is freely filtered and not reabsorbed or secreted, all of
filtered inulin is excreted in urine
 thus, Cinulin is equated with glomerular filtration rate (GFR), and
 Net handling of other substances can be determined, depending on
whether their clearance is
 greater than (indicating net secretion)
 less than (indicating net reabsorption) or
 equal to Cinulin

Renal clearance
Cx = UxV/Px = volume of plasma from which the substance is
completely cleared per unit time
If Cx < GFR: net tubular reabsorption of X
If Cx > GFR: net tubular secretion of X
If Cx = GFR: no net secretion or reabsorption
Cx = clearance of X (mL/min).
Ux = urine concentration of X (eg, mg/mL).
Px = plasma concentration of X (eg, mg/mL).
V = urine flow rate (mL/min).

Glomerular filtration rate
Inulin clearance can be used to calculate GFR b/c it is
freely filtered and is neither reabsorbed nor secreted
GFR = Uinulin x V/Pinulin = Cinulin = Kf [(PGc – PBs) –
(πGC – πBS)]
(Gc = glomerular capillary, Bs = Bowman space)
πBS normally equals zero; Kf = filtration constant.
Normal GFR ≈ 100 mL/min
Creatinine clearance is an approximate measure of GFR
Slightly overestimates GFR b/c creatinine is moderately
secreted by renal tubules
Incremental reductions in GFR define the stages of
chronic kidney disease. Le T and Bhushan V. First Aid for the USMLE Step 1 2016.
NY, New York: McGraw-Hill Education, 2016.

Effective renal plasma flow
 Effective renal plasma flow (eRPF) can be estimated using
para-aminohippuric acid (PAH) clearance b/c between
filtration and secretion there is nearly 100% excretion of
all PAH that enters the kidney
 eRPF = UPAH x V/PPAH = CPAH
Renal blood flow (RBF) = RPF/(1 − Hct)
Plasma = 1 − hematocrit
eRPF underestimates true renal plasma flow (RPF) slightly.

Filtration
 Filtration fraction (FF) = GFR/RPF
 Normal FF = 20%
 Filtered load (mg/min) = GFR (mL/min) x plasma conc.
(mg/mL)
 GFR can be estimated with creatinine clearance
 RPF is best estimated with PAH clearance

Le T and Bhushan V. First Aid for the USMLE Step 1 2016.

Glucose clearance
 Glucose at a normal plasma level (range 60–120mg/dL)
is completely reabsorbed in PCT by Na+/glucose
cotransport
 In adults, at plasma glucose of ∼ 200 mg/dL,
glucosuria begins (threshold)
 At rate of∼ 375 mg/min, all
transporters are fully saturated (Tm)
 Normal pregnancy may decrease ability of PCT
to reabsorb glucose & amino acids
 glucosuria and aminoaciduria
 Glucosuria is an important clinical clue to diabetes
mellitus
 Splay is region of substance clearance between
threshold and Tm due to heterogeneity of nephrons
Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY,
New York: McGraw-Hill Education, 2016.

Nephron physiology: Early PCT
 Early PCT—contains brush border
 Reabsorbs all Glu and AAs and most HCO3– ,
Na+, Cl–, PO4 3–, K+, H2O, and uric acid
 Isotonic absorption
 Generates and secretes NH3, which
acts as a buffer for secreted H+
 PTH—inhibits Na+/PO43– cotransport PO43–
excretion
 AT II—stimulates Na+/H+ exchange 
↑Na+, H2O, and HCO3− reabsorption (permitting
contraction alkalosis)
 5–80% Na+ reabsorbed Le T and Bhushan V. First Aid for the USMLE Step 1 2016.

Nephron physiology: Thin descending loop
of Henle
 Thin descending loop of Henle
passively reabsorbs H2O via
medullary hypertonicity
(impermeable to Na+)
 Concentrating segment
 Makes urine hypertonic
Le T and Bhushan V. First Aid for the USMLE Step 1
2016. NY, New York: McGraw-Hill Education, 2016.

Nephron physiology: Thick ascending
loop of Henle
 Thick ascending loop of Henle-
reabsorbs Na+, K+, and Cl−
 Indirectly induces paracellular
reabsorption of Mg2+ and Ca2+
through ⊕ lumen potential
generated by K+ backleak
 Impermeable to H2O
 Makes urine less concentrated as
it ascends

Nephron physiology: Early DCT
Early DCT—
 reabsorbs Na+, Cl−
 Makes urine fully dilute
(hypotonic)
 PTH—↑Ca2+/Na+ exchange Ca2+
reabsorption

Nephron physiology: Collecting
tubule
Collecting tubule-
 reabsorbs Na+ in exchange for secreting K+ and H+
(regulated by aldosterone)
 Aldosterone—acts on mineralocorticoid
receptor mRNA protein synthesis
 In principal cells: ↑ apical K+ conductance,
↑Na+/K+ pump, ↑ epithelial Na+ channel (ENaC)
activity  lumen negativity ↑ K+ secretion
 In α-intercalated cells: lumen negativity ↑H+
ATPase activity ↑H+ secretion ↑HCO3 −/Cl−
exchanger activity
 ADH—acts at V2 receptor insertion of
aquaporin H2O channels on apical side.

Sodium reabsorption in successive
segments of the nephron
56
Modified from: Pollock CA, Harris D, & Field MJ. The Renal System: Basic Science and Clinical
Conditions 2nd Ed. Elsevier, 2010

57
Nephron Physiology Capsule
Proximal convoluted tubule
• Reabsorbs glucose, amino acids,
water, bicarbonate ions, Na+ and Cl− ions
• Contains a brush border
Thin descending loop of Henle
• Reabsorbs water by medullary
hypertonicity
• It is impermeable to Na+ ions
Thick ascending loop of Henle
• Permeable to Na+ ions
• Impermeable to water
• Contains the Na+/K+/2Cl− transporter
Distal convoluted tubule
• Actively reabsorbs Na+ and Cl− ions
• Simple cuboidal epithelium
Collecting tubule
• Aldosterone: increases the number of
Na+ ion channel in the collecting tubules
• Antidiuretic hormone (ADH): binds to V2
receptors and consequently increases the
number of aquaporins

Volume Regulation
58

Antidiuretic Hormone (ADH)
59
Antidiuretic hormone, also known as arginine vasopressin in
humans, is a 1-kd nonapeptide that is synthesized in
hypothalamus and released into blood from posterior
pituitary gland
 It is structurally similar to oxytocin but is a more potent
(>100 times) antidiuretic
 ADH alters morphology of cells of collecting duct and
increases their permeability

ADH (2)
60
Water passes from collecting duct lumen into renal interstitium,
so an osmotic equilibrium between interstitium and fluid in
duct occurs
In presence of ADH, amount of water that can be reabsorbed
from collecting ducts is limited only by amount flowing through
them
Various stimuli induce ADH release thus production of a
small volume of concentrated urine:
 plasma osmolality, pain, emotion, trauma, and drugs(eg, nicotine,
morphine, ether, some barbiturates)
 ADH is inhibited by ethanol

ADH (3)
61
Note: Normal human reference range of
osmolality in plasma is about 285-295
milli-osmoles per kilogram

Diabetes Insipidus (DI)
62
 Vasopressin is an important regulator of urine osmolarity, as
it increases permeability of collecting ducts in kidney to water
 An inadequate vasopressin effect leads to diabetes insipidus
 Diagnosis of cause of diabetes insipidus is based on
administration of vasopressin
 If there is a pituitary deficiency of vasopressin, administered
vasopressin will increase urine osmolarity central diabetes
insipidus
 If DI is nephrogenic, administered vasopressin will have no effect on
urine osmolarity nephrogenic diabetes insipidus

Diabetes Insipidus (2)
63
 Treatment depends on cause
 If DI is due to a pituitary deficiency, replacement therapy is
instituted
o Vasopressin (Pitressin) can be given intramuscularly, but it
can increase blood pressure due to vasoconstriction
o Lypressin (Diapid), administered intranasally, lasts 4 hours
o Desmopressin (DDAVP), administered intranasally, lasts 12
hours and does not increase blood pressure
• It is also available in tablet form
 If DI is nephrogenic, thiazides (unexpectedly) are effective
treatment

Renin-Angiotensin-Aldosterone System
64
In addition to ADH, a second volume-regulating system-the
RAAS-involves the kidney
Kidneys synthesize and secrete renin, a proteolytic enzyme of
approximately 40 kd, in response to
 decreased blood pressure
 decreased fluid volume, and
 Na+ and increased H+
Renin secretion results in conversion of angiotensinogen (a
blood-borne α globulin produced by the liver) to decapeptide
angiotensin I

RAAS (2)
65
Angiotensin I is converted (primarily in lungs) to angiotensin
II a potent vasoconstrictor and a stimulator of aldosterone
release from adrenal gland
Enzyme that catalyzes conversion of angiotensin I to
angiotensin II, termed angiotensin converting enzyme
(ACE) is target of ACE inhibitor (ACEI) class of
antihypertensive drugs
Angiotensin II and aldosterone stimulate NaCl and water
reabsorption by PCT and collecting duct, respectively

RAAS (3)
66

RAAS (4) Mechanisms of Renin Release
67

Aldosterone production and secretion
controlled through RAAS
68
 Juxtaglomerular (JG) apparatus monitors perfusion pressure of glomerulus
and sodium concentration in distal convoluted tubule (DCT)
 Renin is released in cases of ↓ renal perfusion or ↓ sodium conc. in
DCT Renin cleaves angiotensinogen to angiotensin I Angiotensin-
converting enzyme (ACE) converts angiotensin I to angiotensin II
predominantly in lung Angiotensin II has direct vasoconstrictive effects,
stimulates sodium reabsorption by proximal convoluted tubule (PCT), and
stimulates thirst, antidiuretic hormone (ADH) release, catecholamine
release (Epi & NE), and aldosterone synthesis and secretion 
Aldosterone ↑sodium reabsorption, and as water follows salt, blood
volume ↑along with blood pressure
 Overall these effects act to restore renal perfusion

Aldosterone production and secretion
controlled through RAAS
69Burtis CA, Ashwood, ER & Bruns DE. Tietz Textbook of Clinical Chemistry
and Molecular Diagnostics, 5th Ed, Saunders, 2012.

Renin-Angiotensin-Aldosterone System Capsule
Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

 Renin Secreted by JG cells in response to ↓renal arterial
pressure and renal sympathetic discharge (β1 effect)
 AT II Affects baroreceptor function; limits reflex bradycardia,
which would normally accompany its pressor effects
 Helps maintain blood volume and blood pressure
 ANP, BNP Released from atria (ANP) and ventricles (BNP) in
response to ↑volume; acts as a “check” on RAAS; relaxes
vascular smooth muscle via cGMP ↑ GFR, ↓renin
 Dilates afferent arteriole, constricts efferent arteriole, promotes
natriuresis
 ADH Primarily regulates osmolarity; also responds to low blood
volume states
 Aldosterone Primarily regulates ECF volume and Na+ content;
responds to low blood volume states
RAAS Capsule (2)

See next slide for sources and links further study.
72

Sources and further study:
eLearning
Renal cloud folder tools and resources
MedPharm Guidebook:
Unit 9 Drugs Used to Affect Renal Function
Renal Pharmacology eNotes
Clinical Pharmacology Cases 7, 8, & 55 (Learning Triggers)
Textbooks
Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilman’s The Pharmacological
Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011
Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill,
2012
Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009
Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition.
Philadelphia: Sanders, 2014
Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014.
73

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