Urinary System Urinary Urinary System - Overview: System Major Functions: 1) Removal of organic waste products Kidney from fluids (excretion) 2) Discharge of waste products into the environment (elimination) 1 3) Regulation of the volume / [solute] / pH 3 of blood plasma Ureter

HOWEVER, THE KIDNEY AIN’T JUST FOR PEE’IN… Urinary bladder

• Regulation of blood volume / blood pressure (e.g., renin)

• Regulation of red blood cell formation (i.e., erythropoietin) 2 • Metabolization of vitamin D to active form (Ca++ uptake) Urethra • Gluconeogenesis during prolonged fasting

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figure 25.1

Urinary System Renal ptosis: Urinary System Kidneys drop to lower position due Functional Anatomy - Kidney: to loss of perirenal fat Functional Anatomy - Kidney: Pyelonephritis: Inflammation of the kidney Pyramids appear striped due to parallel arrangement Located in the of capillaries / collecting tubes superior lumbar “Bar of soap” region 12 cm x 6 cm x 3 cm Renal cortex 150 g / kidney Renal medulla

Renal pyramids

Renal papilla

Layers of Supportive Tissue: Renal columns Renal fascia: Peritoneal cavity Outer layer of dense fibrous connective Renal hilum Renal pelvis tissue; anchors kidney in place • Entrance for blood vessels / nerves

Perirenal fat capsule: Major calyx Fatty mass surrounding kidney; cushions Minor calyx kidney against blows Fibrous capsule: Polycystic Transparent capsule on kidney; prevents kidney disease infection of kidney from local tissues (autosomal dominant Kidneys are located retroperitoneal condition)

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figure 25.2 Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figure 25.3

Urinary System Nerve supply to the kidney provided Urinary System via the renal plexus (primarily sympathetic) Functional Anatomy - Kidney: Functional Anatomy - Kidney: Nephron: Functional unit of the kidney Blood Supply to Kidney: (Bowman’s capsule) Glomerular (~ 1 million / kidney; urine formation) • 1/4 of cardiac output delivered to kidneys capsule Distal Cortical radiate • Filter ~ 180 L of blood plasma / day • 0.25 x 5 L / min = 1.25 L / min convoluted vein tubule • Produce ~ 1 - 1.5 L of urine / day Arcuate Proximal 99% of filtrate returned vein Aorta Inferior vena cava convoluted to blood tubule Interlobular vein Nephron Anatomy: Renal artery Renal vein Renal vein 1) Glomerulus Segmental artery Interlobar vein Cortex • Network of capillaries • Tightly wound coil ( surface area) Renal artery Interlobar artery Arcuate vein Medulla Segmental Collecting arteries Arcuate artery Cortical radiate vein duct Interlobular artery Loop of Cortical radiate Portal Peritubular Henle Arcuate artery system capillaries artery

Cortical radiate Afferent Efferent Glomerulus artery arteriole arteriole 2) Renal tubule (capillary) • Location of filtrate (plasma-derived fluid) Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figure 25.4 Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.5 / 25.7

1 Urinary System Urinary System Renal Corpuscle Functional Anatomy - Kidney: (site of filtration) Functional Anatomy - Kidney: Glomerulus + Glomerular capsule

Renal Simple Foot processes Podocyte cell body Filtration Membrane: Efferent corpuscle squamous arteriole epithelium Fenestrated Basement Podocytes endothelium membrane (foot processes)

(-) Afferent arteriole (-) Cortex

Podocyte Medulla (‘foot cell’) ~ 40 nm ~ 90 nm Filtration slit

• Size selectivity (fenestrations / slits) • Charge selectivity (basement membrane) Fenestrated capillaries Glomerular mesangial cells: Degrade macromolecules “hung up” in filtration membrane Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.5 / 25.9 Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.5 / 25.9

Urinary System

Functional Anatomy - Kidney: Proximal Convoluted Tubule (PCT) (major site of filtrate reabsorption) Proximal convoluted tubule Convolutions increase length and enhance filtering ability

• Simple cuboidal epithelium Cortex • Dense microvilli ( surface area) •  mitochondria ( energy demands) Medulla • Infolded basal membrane ( surface area)

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.5

Urinary System Urinary System

Functional Anatomy - Kidney: Functional Anatomy - Kidney: Distal Convoluted Tubule (DCT) & Loop of Henle Collecting Ducts (site of secretion / selective reabsorption) (site of filtrate concentration) Principal cell Thick Segment Distal convoluted Loop of Henle tubule • Similar in structure to the PCT

Thin Segment

Intercalated cell • Simple cuboidal epithelium Cortex Cortex • Simple squamous epithelium • Intercalated cells (acid-base balance) • Freely permeable to water • Principal cells (water / Na+ balance) Medulla Medulla • Smaller lumen;  number of cells (compared to PCT)

Collecting duct

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.5 Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.5

2 Urinary System Urinary System Cortical Juxtaglomerular nephron nephron Functional Anatomy - Kidney: Functional Anatomy - Kidney: Peritubular Juxtaglomerular Apparatus (JGA) capillary (Regulator of filtration rate / systemic blood pressure) Types of Nephrons: • Region where distal end of loop of Henle / DCT lies against afferent arteriole 1) Cortical Nephrons (85%): feeding glomerulus Short loop of • Located in the upper cortex Henle • Primarily involved in reabsorption Cell Types:

1) Juxtaglomerular (granular) cells 2) Juxtamedullary Nephrons (15%): Extraglomerular Macula densa • Bowman’s capsule in lower cortex; loop mesangial • Modified smooth muscle cells (afferent arteriole) cells cells • Prominent secretory granules (renin) of Henle in medulla • Mechanoreceptors; measure blood pressure • Primarily involved in filtrate concentration Vasa recta

2) Macula densa cells Nephron Capillary Beds: • Line loop of Henle / DCT near renal corpuscle Long loop of • Tall cells; nuclei clustered together 1) Peritubular Capillaries: Henle • Chemoreceptors; measure [osmotic] of filtrate • Arise from efferent arterioles 3) Extraglomerular mesangial cells • Closely associate with PCT / DCT • Cluster between macula densa and JG cells 2) Vasa Recta: • Gap junctions; communication (?) Juxtaglomerular cell • Arise from efferent arterioles • Closely associate with loop of Henle Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.8 Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.7

Costanzo (Physiology, 4th ed.) – Figure 6.10 Urinary System (RBF = Renal blood flow) Urinary System Renal Physiology - Overview: RPF = RBF (1 – hematocrit) Glomerular Filtration: Average GFR = 120 – 125 mL / min

In a single day, the kidneys filter 60x the ~ 20% of renal plasma flow (RPF) As in systemic capillaries, the pressures that drive fluid movement is filtered during a pass normal blood plasma volume present across the glomerular capillary wall are Starling pressures • Consume 20 - 25% of all oxygen at rest Starling equation: GFR = Glomerular filtration rate (mL / min) Kf = Hydraulic conductance (mL / min  mm Hg)

Major processes occurring in kidney: PGC = Glomerular capillary hydrostatic pressure (mm Hg) GFR = Kf [(PGC – PBS) – GC] P = Bowman’s space hydrostatic pressure (mm Hg) 1) Glomerular filtration (glomeruli) GS GC = Glomerular capillary osmotic pressure (mm Hg) Net Filtration Pressure Ultrafiltrate: Since filtration of proteins is negligible, All blood borne solutes except proteins BS is removed from equation (= 0) that cross into the tubule system Beginning of glomerular capillary End of glomerular capillary 2) Tubular reabsorption (Tubular network) • Materials reclaimed from filtrate back into the peritubular capillaries

3) Tubular secretion (Tubular network) • Materials moved from peritubular capillaries out into filtrate

Urine: All metabolic waste and unneeded substances; Filtration +16 Results due to change in GC descend collecting ducts to renal pelvis as fluid is filtered out of blood 0 equilibrium Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.10

Urinary System Urinary System Changes in PBS (e.g., kidney stones) and GC (e.g., nephronic syndrome) are often For ease of measure, creatinine Glomerular Filtration: linked with pathologies Clinical Application: (endogenous product) also commonly utilized… Changes in the GFR can be brought about by changes in any of the Starling pressures Glomerular filtration rate is measured by the clearance of a glomerular marker GFR = K [(P – P ) –  ] • Produced by changes in the resistance of the f GC BS GC afferent and efferent arterioles

What makes a good marker?

Constriction of efferent arteriole 1) It must be freely filtered across the glomerular capillaries (no size / charge restrictions) Inulin: Less blood enters Fructose polymer glomerulus  RPF =  PGC =  GFR 2) It cannot be reabsorbed or secreted by the (~5000 daltons) renal tubules 3) When infused, it cannot alter the GFR

Blood backed up in glomerulus Constriction of afferent arteriole . GFR = Glomerular filtration rate (mL / min) [U]inulin x V [U] = Urine concentration of inulin (mg / mL) GRF = inulin [P]. inulin = Plasma concentration of inulin (mg / mL)  RPF =  PGC =  GFR [P]inulin V = Urine flow rate (mL / min)

Costanzo (Physiology, 4th ed.) – Figure 6.11

3 Urinary System Urinary System Q = P / R Glomerular Filtration: Glomerular Filtration:

Renal blood flow, and thus glomerular filtration rate, is autoregulated The major hypotheses explaining renal autoregulation are a over a wide range of mean arterial pressures myogenic mechanism and tubuloglomerular feedback

Myogenic Hypothesis: Tubuloglomerular Feedback: Surface area (6 m2) Relatively fixed… Increased arterial pressure triggers Increased [solute] sensed in DCT; triggers Membrane permeability contraction of vascular smooth muscle contraction of vascular smooth muscle

 renal arterial pressure  renal arterial pressure GFR = Kf [(PGC – PBS) – GC]  GFR Only when renal arterial pressure drops below 80 mm Hg does Recall: RBF decrease Walls of afferent arteriole stretch  solute / water load in DCT

Q = P / R 1) Na+ / Cl- What is detected? 2) Ca2+ Thus, changes in pressure must be 3) Total osmolarity countered with changes in resistance Stretch-activated Ca2+ gates open Macula densa cells detect change; send signal

1) adenosine What signal is sent? 2) prostaglandins For renal autoregulation, it is believed that resistance is controlled 3) kinins primarily at the level of the afferent arteriole Afferent arteriole constricts;  resistance Afferent arteriole constricts;  resistance

Costanzo (Physiology, 4th ed.) – Figure 6.6

Urinary System To protect against potential renal failure, Urinary System prostaglandins are produced locally during Glomerular Filtration: stressful events and vasodilate both arterioles

In addition to autoregulation, extrinsic factors also contribute If the ultrafiltrate produced during glomerular filtration in a single day were to renal blood flow regulation excreted from the body unmodified, what would be lost in urine?

1) Sympathetic Nervous System 2) Angiotensin II Ultrafiltrate / day = 180 L (and circulating catecholamines) • Potent vasoconstrictor of both afferent • Sympathetic nerve fibers innervate and efferent arterioles Substance Amount both afferent and efferent arterioles HOWEVER • Activate 1 receptors Water 180 L (180 kg) • Trigger vasoconstriction + • Efferent arteriole more susceptible than Na 25,200 mEq (580 g) the afferent arteriole - (701 g) HOWEVER Cl 19,800 mEq - THUS HCO3 4320 mEq (264 g) • More  receptors on afferent arterioles 1 Glucose 14.4 g Low levels of angiotensin II =  RBF =  GFR THUS BUT  Sympathetic input =  RBF =  GFR Each of the above losses represents High levels of angiotensin II =  RBF =  GFR more than 10-fold the amount present in the entire extracellular fluid of the body

Urinary System Urinary System A majority of other major nutrients (e.g., amino acids / vitamins) reabsorbed by Tubular Reabsorption: Tubular Reabsorption: PCT using similar mechanism Water and many solutes (e.g., Na+) are reabsorbed from the filtrate into the peritubular capillaries via Glucose is a good example for examining the basic underlying membrane transporters mechanisms of tubular reabsorption of nutrients

Filtered Load: Glucose: Amount of a substance filtered into Bowman’s space per unit time • Reabsorbed in proximal convoluted tubule

[P] = Plasma concentration of X X Two-step Process:

Filtered LoadNa+: Filtered load = GFR x [P]X 1) Na+-glucose cotransport 180 L / day x 140 mEq / L • Occurs at luminal membrane ‘Downhill’ 25,200 mEq / day Excretion Rate: Amount of a substance excreted • Na+-glucose cotransporter (SGLT) in urine per unit time • Secondary active transport ‘Downhill’ [U] = Urine concentration of X X . 2) Facilitated glucose transport ‘Uphill’ Excretion RateNa+: Excretion rate = V x [U]X • Occurs at peritubular membrane  glucose  glucose  glucose 1 L / day x 100 mEq / L • GLUT 1 / GLUT 2 transporters 100 mEq / day Reaborption rate: • Facilitated diffusion Filtered load - Excretion rate (99.4% of filtrate load) Reabsorption Rate = 25,200 - 100 = 25,100 mEq / day Filtered load must be greater than excretion Na+ rate for net reabsorption to occur

Costanzo (Physiology, 4th ed.) – Figure 6.12 Costanzo (Physiology, 4th ed.) – Figure 6.14

4 Urinary System Glucosuria: Urinary System Diabetes mellitus? Tubular Reabsorption: During pregnancy? Tubular Reabsorption: A glucose titration curve depicts the relationship between plasma Along with nutrients, the reabsorption of ions is an important glucose concentration and glucose reabsorption component of nephron physiology

Things to Note:

The Tm for glucose is approached gradually • As the plasma [glucose] increases, the • Nephron heterogeneity filtered load increases linearly • Low affinity • All glucose can be reabsorbed up to plasma [glucose] of 200 mg / dL Sodium (Na+): • Single most abundant cation in filtrate Transport Maximum (Tm): • 80% of active transport energy devoted Point at which all transport proteins to Na+ reabsorption are fully engaged (saturated) • Net reabsorption of > 99% of filtered load Glucosuria Glucose Tm = 350 mg / dL

• Glucose starts to appear in the urine at plasma [glucose] above 200 mg / dL

Costanzo (Physiology, 4th ed.) – Figure 6.15 Costanzo (Physiology, 4th ed.) – Figure 6.19

Urinary System Urinary System

Tubular Reabsorption: Tubular Reabsorption:

Sodium (Na+) Reabsorption Sodium (Na+) Reabsorption

Early PCT

Late PCT Active transport of Na+ drives system CELLULAR ROUTE Lumen-negative potential: Co-transport of Na+- glucose and + (100%) Na - amino acid bring (+) charge Lumen-positive potential: in while leaving (-) in lumen Movement of Cl- down its [gradient] leaves (+) charges in filtrate  [Cl-] (50%) (100%)

Na+ follows Cl- through tight junctions (~ 100%) driven by lumen-positive potential

(85%) PARACELLULAR ROUTE ‘Tight’ junctions permeable to small ions “Highest priority” reabsorptive work Costanzo (Physiology, 4th ed.) – Figure 6.20 Costanzo (Physiology, 4th ed.) – Figure 6.21

Urinary System Urinary System

Tubular Reabsorption: Tubular Reabsorption:

Solute and water reabsorption are coupled and are proportional Sodium (Na+) Reabsorption to each other in the PCT – Isosmotic reabsorption Na+ moves freely into / out of the thin portions of the loop of Henle but there is no net reabsorption

Lumen-positive potential Isosmotic Reabsorption: Thick Ascending Limb 1) Na+ enters cell; water follows passively

2) Na+ actively pumped out of basolateral Na+-K+-2Cl- membrane; water follows passively cotransporter Reabsorption mechanism is load-dependent; the more Na+ 3) Isosmotic fluids collect in lateral intra- delivered to the region, the more cellular space; high osmotic pressure the region reabsorbs in peritubular capillary drives reabsorption

The most potent diuretics, loop diuretics, work at this site (block cotransporters) 67% of solute absorbed in PCT Na+-K+-2Cl- 67% of water absorbed in PCT cotransporter (Diuretic = Drug that elevates rate of urination) electrogenic • Furosemide Can block up to 25% of Water is NOT reabsorbed with solutes • Bumetanide Na+ reabsorption in this region (diluting segment)

Costanzo (Physiology, 4th ed.) – Figure 6.22 Costanzo (Physiology, 4th ed.) – Figure 6.24

5 Urinary System Urinary System

Tubular Reabsorption: Tubular Reabsorption:

Sodium (Na+) Reabsorption Sodium (Na+) Reabsorption

Like the loop of Henle, the DCT and collecting duct Like the loop of Henle, the DCT and collecting duct exhibit load-dependent Na+ reabsorption exhibit load-dependent Na+ reabsorption

(only 3% Na+ reabsorbed; fine-tuning) Early Distal Tubule Late distal tubule / Collecting duct

Epithelial Na+ Na+-Cl- channels (ENaC) Aldosterone regulates activity in cell: cotransporter 1)  ENaC proteins

(Amiloride) 2)  Na+-K+ ATPase 3)  enzymes (citric acid cycle)

NaCl reabsorption inhibited by NaCl reabsorption inhibited by thiazide diuretics (block cotransporters) PRINCIPAL CELL K+-sparing diuretics (block ENaCs)

Water is NOT reabsorbed with solutes Water reabsorption is variable in this region (cortical diluting segment) (hormone dependent)

Costanzo (Physiology, 4th ed.) – Figure 6.25 Costanzo (Physiology, 4th ed.) – Figure 6.26

Urinary System Urinary System

Tubular Secretion: A few substances (e.g., organic acids / bases) Tubular Reabsorption: are secreted from peritubular capillary blood into tubular fluid by way of A PAH titration curve depicts the relationship between plasma membrane transporters PAH concentration and PAH secretion

10% bound to blood proteins Filtered Load: Amount of a substance filtered into Bowman’s space per unit time

[P]X = Plasma concentration of X Para-aminohippuric acid (PAH) Filtered LoadPAH: Filtered load = GFR x [P]X

180 L / day x 0.1 g / L Things to Note: 18 g / day Excretion Rate: Amount of a substance excreted • As the plasma [PAH] increases, the in urine per unit time filtered load increases linearly [U] = Urine concentration of X X . • As with reabsorption, a transport Excretion RatePAH: maximum exists for PAH Excretion rate = V x [U]X 1 L / day x 54 g / L • Separate transporters exist • At [low] PAH, steep excretion rate; at 54 g / day for organic bases (e.g., morphine) [high], rate declines as T reached Secretion rate: m Excretion rate - Filtration load Also transport antibiotics (e.g., penicillin) Secretion Rate = 54 - 18 = 36 g / day Excretion rate must be greater than filtration PAH load for net secretion to occur • Transporters for PAH located in peritubular capillaries of PCT Costanzo (Physiology, 4th ed.) – Figure 6.12 Costanzo (Physiology, 4th ed.) – Figure 6.17

Urinary System Urinary System

Tubular Reabsorption / Secretion: Tubular Reabsorption:

Along with nutrients, the reabsorption / secretion of ions is an important Potassium (K+) Reabsorption / Secretion component of nephron physiology The distal convoluted tubule and collecting ducts are responsible For the fine adjustments to K+ reabsorption / secretion

K+ reabsorption is handled by the K+ reabsorption is handled by the -intercalated cells principal cells Potassium (K+): • Balance essential for excitable tissue function • Utilizes both reabsorption and secretion mechanisms for regulation

H+-K+ Aldosterone down ATPase down increases [gradient] + electrochemical K secretion gradient

Relatively uncommon; most often Associated with individuals having associated with low K+ diet normal / high K+ diet The magnitude of K+ secretion is determined by the size of the electrochemical gradient

Costanzo (Physiology, 4th ed.) – Figure 6.30 Costanzo (Physiology, 4th ed.) – Figure 6.31

6 Urinary System Urinary System

Tubular Reabsorption / Secretion: Tubular Reabsorption / Secretion:

Along with nutrients, the reabsorption / secretion of ions is an important Along with nutrients, the reabsorption / secretion of ions is an important component of nephron physiology component of nephron physiology

Filtered LoadCa2+: Only 60% available 180 L / day x 5 mEq / L x 0.6 for filtering

540 mEq / day

- Phosphate (HPO4 ): • Important ion for bone and as a urinary buffer for H+ Only reabsorbed via paracellular • Only reabsorbed at PCT route (lumen-positive potential) Parathyroid hormone blocks reabsorption Calcium (Ca2+): + • G-protein coupled system inhibits Na -phosphate • Important ion for bone and excitable tissue Loop diuretic cotransport leaving phosphate in tubule lumen function (used to treat hypercalcemia) • Pattern of reabsorption similar to sodium Psuedohypoparathyroidism: • Regulation of Ca2+ occurs at DCT Although circulating levels of PTH are high, PTH cannot produce its phosphaturic effects due to renal cells being resistant to PTH action

Costanzo (Physiology, 4th ed.) – Figure 6.32 Costanzo (Physiology, 4th ed.) – Figure 6.32

Urinary System Urinary System

Regulation of Urine Volume / Concentration: Regulation of Urine Volume / Concentration:

The kidneys keep the solute load of body fluids constant, The kidneys keep the solute load of body fluids constant, at about 300 mOsm at about 300 mOsm

1) Countercurrent Multiplication Corticopapillary osmotic gradient: A gradient of osmolarity in the interstitial fluid A function of the loops of Henle, which deposit NaCl of the kidney from the cortex to the papilla in the deeper regions of the medulla rhat allows the kidney to vary urine concentration / volume

What solutes contribute to Things to Recall: the osmotic gradient? 1) The thick, ascending limb of the loop What mechanisms deposit these of Henle reabsorbs NaCl Na+-K+-2Cl- solutes in the interstitial fluid? cotransporter 2) The thick, ascending limb of the loop 1) Countercurrent multiplication of Henle is impermeable to water 2) Urea recycling

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.15 Costanzo (Physiology, 4th ed.) – Figure 6.37

Urinary System Urinary System The size of the corticopapillary gradient Note: Regulation of Urine Volume / Concentration: depends on the length of the loop of Henle Regulation of Urine Volume / Concentration: Constant 200 mOsm difference between (Humans = 1200 mOsm) two limbs of the loop of Henle 1) Countercurrent Multiplication 1) Countercurrent Multiplication • Limit of NaCl pump power

Step 2: ~ 40 L SINGLE EFFECT ~ 200 L Step 1: New fluid (300 mOsm) enters descending limb from PCT NaCl reabsorbed from Equal volume displaced from ascending loop ascending limb Cortex ~ 20 L Descending limb equilibrates H2O NaCI with interstitial fluid High osmolarity TUBULAR H2O NaCI fluid “pushed” FLOW down H2O NaCI

Outer H O NaCI 2 medulla

H2O TUBULAR SINGLE NaCI FLOW EFFECT H2O

H2O Inner medulla

Costanzo (Physiology, 4th ed.) – Figure 6.37 Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.16

7 Costanzo (Physiology, 4th ed.) – Figure 6.39 Urinary System Urinary System

Regulation of Urine Volume / Concentration: Regulation of Urine Volume / Concentration:

The kidneys keep the solute load of body fluids constant, The vasa recta are specialized capillary beds that serve the at about 300 mOsm medulla and papilla of the kidney

2) Urea Recycling Vasa recta participates in countercurrent exchange • Countercurrent multiplier established gradient (active process) A function of the collecting ducts, which deposit urea in the deeper regions of the medulla • Countercurrent exchange maintains gradient (passive process)

BV

• Only 5% of renal blood flow Things to Recall: serves medulla (‘sluggish’ flow) Urea enters the interstitial fluid via diffusion from 1) The thick, ascending limb of the loop • Capillaries permeable to both water and solutes the inner medullary collecting ducts and of Henle reabsorbs NaCl Na+-K+-2Cl- Replaced via moves down gradient into ascending cotransporter countercurrent limb of loop of Henle via multiplier Vasa facilitated diffusion 2) The thick, ascending limb of the loop recta of Henle is impermeable to water Capillary osmolarity matches interstitial osmolarity Picks up water additional lost from the loop of Henle

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.16 Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.7

Urinary System Urinary System Occurs when circulating levels of Occurs when circulating levels of Regulation of Urine Volume / Concentration: ADH are high Regulation of Urine Volume / Concentration: ADH are high

Dilute or concentration urine can be formed depending on the Dilute or concentration urine can be formed depending on the presence / absence of antidiuretic hormone (ADH) presence / absence of antidiuretic hormone (ADH)

~ 180 L Formation of Concentrated Urine (~ 1200 mOsml) ~ 180 L Formation of Concentrated Urine (~ 1200 mOsml)

• 1 ml fluid / min produced (~ 1.5 L urine / day) • 1 ml fluid / min produced (~ 1.5 L urine / day) ~ 20 L ~ 20 L 1) The PCT pulls out solutes and water in equal 4) In late DCT, the principle cells are permeable proportions (~ 67%) to water in the presence of ADH ~ 60 L ~ 60 L Remember: Isosmotic reabsorption V2 receptor

2) The thick, ascending limb of the loop of Henle Lumen H2O actively reabsorbs NaCl (Na+-K+-2Cl- cotransporter); 80 mOsm cells impermeable to water H2O ADH increases activity of Na+-K+-2Cl- cotransporters

H2O leading to enhanced single effect (e.g., steeper gradient)

(Na+-Cl- cotransporter) H2O 3) In early DCT, NaCl reabsorbed ; cells impermeable to water Blood Aquaporin 2 H2O 300 mOsm Filtrate osmolarity reduced to ~ 80 mOsm

Costanzo (Physiology, 4th ed.) – Figure 6.41 Costanzo (Physiology, 4th ed.) – Figures 6.40 / 6.41

Urinary System Urinary System Occurs when circulating levels of Occurs when circulating levels of Regulation of Urine Volume / Concentration: ADH are high Regulation of Urine Volume / Concentration: ADH are low

Dilute or concentration urine can be formed depending on the Dilute or concentration urine can be formed depending on the presence / absence of antidiuretic hormone (ADH) presence / absence of antidiuretic hormone (ADH)

Formation of Dilute Urine (~ 75 mOsml) ~ 180 L Formation of Concentrated Urine (~ 1200 mOsml) ~ 180 L • 15 – 19 ml fluid / min produced (~ 22.5 L urine / day) • 1 ml fluid / min produced (~ 1.5 L urine / day) ~ 20 L ~ 20 L 1) The PCT pulls out solutes and water in equal 5) In collecting duct, the principle cells are also proportions (isosmotic reabsorption) permeable to water in the presence of ADH ~ 60 L ~ 60 L 2) The thick, ascending limb of the loop of Henle ADH increases urea recycling in the inner medullary actively reabsorbs NaCl (Na+-K+-2Cl- cotransporter); collecting duct via the insertion of cells impermeable to water urea UT1 transporters H2O Corticopapillary osmotic gradient diminished in absence of ADH ( transporter activity) • Urea flows down concentration gradient; H2O enhances corticopapillary osmotic gradient 3) In early DCT, NaCl reabsorbed (Na+-Cl- cotransporter); Urea H2O cells impermeable to water

H2O 4) Late DCT collecting ducts impermeable to Urea H2O water; limited NaCl reabsorbed Limited urea recycled ~ 20 L ~ 1.5 L Costanzo (Physiology, 4th ed.) – Figure 6.41 Costanzo (Physiology, 4th ed.) – Figure 6.42

8 Urinary System Urinary System

Regulation of Urine Volume / Concentration: Pathophysiology:

Diuretics are chemicals that elevate rates of urination Conditions which affect ADH release / action can lead to abnormal urine flow rates

Pharmacological Drugs: • Treat hypertension / edema Inappropriate Formation of Inappropriate Formation of Most potent Dilute Urine Concentrated Urine 1) Loop diuretics diuretic (tumor) • Block Na+ reabsorption in Central Diabetes Insipidus: thick, ascending loop of Henle Circulating levels of ADH abnormally low Furosemide

Weak diuretic; Cause: Treatment: Targets PCT Trauma / Drugs which act as ADH 2) Thiazide diuretics tumor analogues (e.g., dDAVP) • Block Na+ reabsorption in early distal convoluted tubule Nephrogenic Diabetes Insipidus: Isoren Circulating levels of ADH normal; principal cells of kidney unresponsive to hormone Syndrome of Inappropriate ADH (SIADH): Weak diuretic; Circulating levels of ADH abnormally high + 3) K sparing diuretics Blocks ADH release Cause: Treatment: • Block Na+ reabsorption in late Defect in 2nd messenger Thiazide diuretics; triggers  Cause: Treatment: DCT / collecting ducts system (e.g., genetic) water reabsorption in PCT Trauma / Drugs which block ADH Amiloride tumor activity (e.g., demeclocyline) Costanzo (Physiology, 4th ed.) – Figure 6.41

Urinary System Urinary System Incontinence: Urine: Micturition: The inability to voluntarily control micturition

Urochrome: Pigment produced by gut flora; waste product of RBC destruction

Physical Characteristics of Urine:

1) Color & Transparency Dilute = clear / pale yellow 95% water Concentrated = deep yellow 5% solutes 2) Odor • Nitrogenous wastes Fresh = slight odor (urea > creatinine > uric acid) Reflexive urination Old = ammonia-like odor (e.g., toddler) • Ions (e.g., Na+; K+; phosphates) (bacterial metabolism)

3) pH (bladder usually voided before Acidic (pH ~ 6) 400 mL collects) (~ 10 mL remains following voiding)

Marieb & Hoehn (Human Anatomy and Physiology, 8th ed.) – Figures 25.22

9