Renal Flashcards

Question

TBW Ionic Compositions

Answer 1

ECF: High [Na⁺] & low [K⁺] ICF: Low [Na⁺] & high [K⁺] Distribution of Na⁺ and K⁺ due to the Na/K-ATPase.

Answer 2

Compound known to evenly distribute through compartment of interest used to determine compartment volumes. At equilibrium, plasma concentration measured. Volume determined from: **Volume = amount of indicator / [indicator]** Measured using: * _TBW_ * heavy water (D₂O) * antipyrene * _ECF_ * impermeant ions * Na⁺ * radioactive ³⁵SO₄ * inert sugars * mannitol * sucrose * inulin * _ICF_ * difference between TBW and ECF

Answer 3

**Volume expansion** and **volume contraction** refers to ECF volume changes. Normal: _Width = volume_ 2/3 ICF and 1/3 ECF _Height = solute concentration as osmolatity_ Osmolality of both compartments 285 mOsm/kg **When NaCl is added to the ECF, all of the NaCl remains in the ECF.**

Answer 4

**2 L of pure water added to ECF** * TBW increased 42 L → 44 L * Osmolality decreased due to dilution * Water moves ECF → ICF to maintain osmotic eq. * 2/3 water added ends up in ICF

Answer 5

**2 L of isotonic saline (0.9% NaCl) added to ECF.** * TBW increases 42 L → 44 L * Osmolality of ECF unchanged * No net water movement * Only ECF volume increases * No change in osmolaity in either compartment

Answer 6

1 L of concentrated NaCl (5% NaCl) added to ECF. * TBW increases 42 L → 43 L * ECF osmolality increases * Water moves ICF → ECF until osmotic gradient eliminated * ICF volume decreases * ECF volume increases * Osmolality of both compartments increased

Answer 7

* Commonly seen after viral gastroenteritis * Water lost but kidneys maintain ECF [Na⁺] in normal range * ECF volume falls * No net water movement * All of the volume loss from ECF

Answer 8

* Lost in the desert without water * Assume that only water is lost → **TBW decreased** * **ECF volume decreased → osmolality increases** * Water moves from **ICF → ECF** until equilibrium * Both **ECF & ICF volumes decreased** * 2/3 ICF & 1/3 ECF **distribution maintained** * **Osmolality** in both compartents equal or greater than before

Answer 9

* Seen with adrenal insufficiency * Reduced aldosterone production * Decreased renal absorption of Na⁺ * Slightly decreased water reabsorption → net water loss → reduced TBW * **ECF volume and [Na⁺] decreased** * **Osmolality ICF \> ECF** * Water moves **ECF → ICF** * After equilibrium: * **TBW and ECF volumes reduced** * **ICF volume increased** * **Osmolality of ECF and ICF lower**

Answer 10

Glomerular and peritubular capillaries form an **arterial portal system**. * Glomerular capillaries sit in Bowman's capsule. * Peritubular capiilaries warps around tubules. * Cells lining tubules reabsorb solutes/water from filtrate or secrete into them. Renal artery ⇒ afferent arteriole ⇒ glomerular capillary bed ⇒ efferent arteriole ⇒ peritubular capillary bed ⇒ renal vein.

Answer 11

Composed of 3 layers: 1. **_Capillary endothelium_** * **Fenestrated** * Minimally-selective openings 70-100 nm diameter * **Negative surface charge** ⇒ inhibits passage of negatively charged solutes 2. **_Basement membrane_** * Secreted by both endothelium and epithelium * **Type IV collagen** * Inhibits passage of _intermediate to large sized_ molecules * **Negatively charged extracellular matrix material** * Restricts passage of _negatively charged molecules_ 3. **_Epithelial layer_** * Made of **podocytes** * Specialized epithelial cells * Foot processes with secondary toe-like **pedicles** * **Slit diaphrams** between pedicles * _Pedicles & slit diaphragms_ with **negative surface charge** * Inhibits passage of _large negatively charged molecules_ * Slit diaphragms connected to **contractile elements** in podocytes * Permits _control over epithelial permability_

Answer 12

* **Filtered fluid from glomeruli enters nephron for further processing** * Glomerulus serves as molecular sieves * water, electrolytes, and solutes with MW \< 5,200 freely filtered * Variably filtered substances with MW 6,000 to 60,000 * Permeability related to size, shape, and charge

Answer 13

Forces that govern fluid movement across glomerular capillary described by Starling's Law: **GFR = K_f[(P_GC + π_BS) - (π_GC - P_BS)]** K_f = filtration coefficient P_GC = hydrostatic pressure of glomerular capillary P_BS= hydrostatic pressure of Bowman's space π_GC= oncotic pressure of glomerular capillary π_BS= oncotic pressure of Bowman's space ⇒ 0 since proteins are not passed through the capillary

Answer 14

**Net force for fluid movement (P_UF) at glomerular capillaries approximately + 10 mmHg.** Fluid pushed out of the capillary. * **P_BSand π_BS** constant under normal conditions * **π_GC** higher at _efferent arteriole_ than afferent * Due to ~15-20% volume loss by blood * **Capillary hydrostatic pressure (P_GC)** is the main driving force for filtration * P_GCat afferent arteriole higher than other capillary beds * At start of renal arterial portal system * **Small pressure drop** exists along the capillary * P_GC@ afferent arteriole ~ 60 mmHg * P_GC@ efferent arteriole ~ 58 mmHg * Depends on * aortic pressure * renal arterial pressure * afferent and efferent arterial resistance

Answer 15

**_Afferent arteriole_** * **Constriction** _decreases_ glomerular blood flow * **Dec. P_UF and GFR** * **Dilation** _increases_ glomerular blood flow * **Inc. P_UF and GFR** **_Efferent arteriole_** * **Constriction** _decreases_ glomerular blood flow * Causes _pressure to back up in capillary bed_ ⇒ inc P_GC * **Inc. P_UF and GFR** * **Dilation** _increased_ glomerular blood flow * Causes drop in P_GC * **Dec. P_UF and GFR**

Answer 16

Ensures that RBF and GFR remains relatively stable over a wide range of MAPs (80-180 mmHg). Minimalizes the impact of changing arterial pressure on Na⁺ excretion. **1. Myogenic Response** **2. Tubuloglomerular feedback (TGF)**

Answer 17

_Auto-regulatory Mechanism_ * **Increase in pressure** results in vascular **contraction** to **maintain a constant blood flow** * Mediated by **stretch-activated cation channels** * Opens in response to increased translumenal pressure * Depolarizes smooth muscle cells * Elicits contraction * Found only in **afferent arterioles**

Answer 18

_Auto-regulatory mechanism_ unique to the kidneys. * Mediated by the macula densa * Part of the juxtaglomerular apparatus * In the thick ascending limb at the transition of the LoH to the distal convoluted tubule * **Macula densa cells monitor local Na⁺ and Cl^- concentrations** * Increased P_GC ⇒ Increased GFR ⇒ Increased NaCl delivery to macula densa * Cells release **ATP ⇒ adenosine** * **Adenosine** binds to: * **A₁ purine receptor**s on _afferent arterioles_ * **Vasoconstriction** * Reduces blood flow & GFR * **A₂ purine receptors** on _efferent arterioles_ * **Vasodilation** * Increases outflow * Decreases P_UF & GFR **_At high flow rates:_** Increased NaCl delivery to macula densa ⇒ ATP ⇒ adenosine production ⇒ **afferent arteriole constriction** & **efferent arteriole dilation** AND **renin release from granular cells inhibited** ⇒ decreased P_UF & GFR. **_At low flow rates:_** Decreased NaCl delivery to macula densa ⇒ no adenosine made ⇒ **inhibition of renin release removed** ⇒ renin starts RAAS cascade ⇒ increased P_UF & GFR.

Answer 19

1. Drop in blood pressure triggers **carotid and aortic baroreceptor reflex** 2. SNS activation results in release of **norepinephrine** 3. Leads to **vasoconstriction** * **Efferent arterioles more sensitive to norepi** * **Mild SNS** activation **preferentially constricts efferent arterioles** * Results in reduced RBF **maintaining GFR** * **Intense SNS** activation **constricts both affrent and efferent arterioles** * **Reduces GFR** * Severe hemorrhage causes prolonged constriction of renal arterioles * Can lead to renal ischemia and failure

Answer 20

* Low MAP pressures triggers **renin** release from _granular cells of JGA_ * Renin converts Angiotensinogen ⇒ Angiotensin I * ⇒ Angiotensin II by ACE in lungs * **Ang II** is a **potent vasoconstrictor** * Stronger effect on **efferent arteriole** compared to afferent * Net effect that **GFR increases and RBF decreases** * Ang II also induces _renal production_ of **prostaglandin vasodilators PGE₂ and PGI₂** * PGE₂ and PGI₂_preferentially_ **dilates afferent arteriole** * counterbalances constriction of afferent arteriole by Ang II * Ensures that RBF is not decreased too much

Answer 21

Substances can cross the renal epithelial barrier via two pathways: 1. **_Paracellular route_** * Movement between cells in the epithelia * Permeability depends upon tightness of intercellular junctions * Mostly water with associated solvent drag 2. **_Transcelluar route_** * Movement across the apical and basolateral membranes of epithelial cells * Usually requires a channel or transporter in each membrane * Solute and water transport depends on * presence of channel/transport * distribution along nephron * location in basolateral/apical membrane * Example aquaporins: * Always present in proximal tubule and descending thin limb of LoH * Controlled expression by ADH/AVP in collecting ducts

Answer 22

* **_Electrochemical Na⁺ gradient_** * Set up by the **basolateral Na/K-ATPase** * High [Na⁺] in lumen * Low intracelluar [Na⁺] * _Transmembrane potential ~ 70 mV_ * **Major driving force** for solute and water movement * Drives movement of _Na⁺ into epithelial cells_ * Then pumped into interstitial space & returned to circulation * **_Transepithelial potential_** * Also set up by the Na/K-ATPase * **~ 3 mV with lumen negative** * Driving force for movement of _anions via paracellular pathway_ * **_Osmotic gradient_** * Na/K-ATPase: 3 Na⁺ out for every 2 K⁺ in from insterstitial space * Drives _water movement across epithelial barrier_ for water reabsorption * _Transcellular_ via aquaporins * _Paracellular_ via intercellular junctions * Water movement can sweep ions and small organic molecules with it ⇒ **solvent drag**

Answer 23

* Transporters exhibit saturation at high solute concentrations * Maximal transport rate ⇒ **tubular transport maximum (T_m)** * As [solute] reaches T_m, not all solute reabsorbed and some excreted in urine. * Solutes begin appearing in urine before T_m reached ⇒ **splay** * Represents heterogeneity in transporter distribution and function * As [solute] increases, urine concentration increases

Answer 24

Uses both _transcellular_ and _paracellular_ pathways. Tight junctions are highly permeable to H₂O, Na⁺, K⁺, Cl^-. Unable to maintain Na⁺ and K⁺ gradient. **PCT reabsorption is isosmotic.** * **_Reabsorbs:_** * Essentially all filtered **glucose and amino acids** * Largest fraction (~ 70%) of filtered: * **Na⁺** * **K⁺** * **Ca²⁺** * **Cl^-** * **HCO₃^-** * **_Secretes:_** * Various organic **cations and anions** * **_Synthesizes and excretes:_** * **NH₃/NH₄⁺** * Role in HCO₃^- generation & acid/base regulation

Answer 25

70% of the Na⁺ that enters PCT is fully reabsorbed. * **_Transcellular_** * _Basolateral_ * **Na/K-ATPase** * sets up Na⁺ gradient * sets up transmembrane potential * starts process of Na⁺ reabsorption * **Na⁺/HCO₃^- cotransporter** * _Apical_ * Various **Na⁺ coupled transporters** * glucose * amino acid * phosphate * organic acid * **NHE3** **Na⁺/H⁺ exchanger** * **_Paracellular_** * Driven by the **transepithelial potential** (- 3 mV in lumen) * **Cl^-** from lumen ⇒ interstitial space * Some reabsorbed Na⁺ can leak back to lumen

Answer 26

* **_Reabsorption:_** * **Transcellular** * Aquaporins always present in PCT * **Paracellular** * Movement of Na⁺ and other solutes creates a **temporary osmotic gradient** * PCT epithelium very water permeable * Drives water movement **from** **lumen across epithelial layer** * Water that enters _interstitial space_ is absorbed by **peritubular capillaries**. * Capillary oncotic pressure (**π_PC**) \> capillary hydrostatic pressure (**P_PC**) * Water _moves into_ the capillary

Answer 27

**PCT is the main site for bicarb recovery (~80%).** * HCO₃^- charged & cannot diffuse across cell * No HCO₃^- transporters on apical membrane * PCT secretes **H⁺** into _lumen_ using **NHE3 Na⁺/H⁺ exchanger** * **H⁺** converts **HCO₃^-** into **H₂CO₃** * **Carbonic anhydrase IV** converts **H₂CO₃** to **CO₂ and H₂O** * CO₂ and H₂O easily enters the cell. * Inside, **carbonic anhydrase II** converts **CO₂** back to **H⁺** and **HCO₃^-**. * H⁺ re-enters lumen via _NHE3 Na⁺/H⁺ exchanger_ * **HCO₃**^-moved to _interstitial space_ by **Na⁺/HCO₃^- cotransporter**.

Answer 28

* **_Enters the cell (apical)_** * **Paracellular** * _Throughout PCT_ * Driven by postive transepithelial potential * **Transcellular** * Only in the _proximal straight tubule (PST)_ * **Cl^-/base exchanger (CFEX)** * **_Leaves to interstitial space (basolateral)_** * Cl^- channel * K/Cl co-transporter As Cl^- is reabsorbed, H₂O crosses to a greater extent. Luminal [Cl^-] in tubular fluid rises slightly as fluid moves down the PCT.

Answer 29

* Mainly through passively movement * **Paracellular** * **Solvent drag** in response to water movement

Answer 30

~ 70% of filtered free Ca²⁺ reabsorbed in the PCT. Passive and paracellular.

Answer 31

~ 80% of filtered P_i absorbed in PCT Rate of transport depends on plasma [P_i] and parathyroid hormone (PTH). **Mechanism:** * _Apical_ absorption via 2 different **Na⁺-phosphate cotransporters**: * **NaP_i IIc** * **NaP_i IIa** * Basolateral membrane mechanism unknown **_Regulation:_** * Transporters with **higher affinity for HPO₄^2-** than for H₂PO₄^- * **pH of plasma** affects reabsorption of P_i * **acidosis reduces reabsorption** * **High plasma [P_i]** causes **PTH release** * PTH promotes **endocytosis and degradation of apical P_i transporters** * More P_i excreted * **Low plasma [P_i]** * **Increased transporter density** on apical membrane * Increased reabsorption of P_i

Answer 32

_Hemodynamic changes_ that **alter GFR** _modulate_ the **rate of Na⁺** (and Cl^-) **reabsorption**. * **At normal GFR**: * Low P_PC and high π_PC ⇒ net fluid uptake into capillaries. * **Increased GFR** due to _dec. AA resistance_ and _inc. EA resistance_: * More fluid filtered * Peritubular protein content increases ⇒ **inc. π_PC** * Hydrostatic pressure in peritubular capiilar decreases ⇒ **dec. P_PC** * Net effect is **increased driving force for fluid movement** from _interstitial space ⇒ peritubular capillary_ * **Enhances absorption of fluid and NaCl**

Answer 33

**_Neurohumoral stimuli:_** * Affects GFR and RPF * Via constriction/dilation of afferent and efferent arterioles * Affect specific transporters in the kidney * Affects Na⁺ reabsorption * Hemodynamic changes have a greater effect than transporter-specific effects

Answer 34

* Three sections: 1. **Descending thin limb (DTL)** 2. **Ascending thin limb (ATL)** 3. **Thick ascending limb (TAL)** * Thin limb walls: * Very simple cellular structure * Designed to move filtered fluid through the renal medulla * Thick ascending limb: * Specialized for transport * Numerous ion pumps * Contains many mitochondria

Answer 35

**LoH extracts water and ions which were not reabsorbed in the proximal tubule.** 70% of filtered Mg²⁺ 25-30% of filtered Ca²⁺ 25% of filtered Na⁺ 15% of filtered HCO₃^- ~10% of filtered K⁺ ~10% of filtered water **Each section has varied permeability and functions.** * **Descending thin limb (DTL):** * no Na⁺ or Cl^- transport * very water permeable * **Ascending thin limb (ATL):** * passive Cl^- transport * passive Na⁺ absorption * water impermeable * **Thick ascending limb (TAL):** * active Na⁺, K⁺, and Cl^- transport * water impermeable

Answer 36

Hairpin-like structure of LoH and vasa recta coupled with the permeability properties of the various regions generates the **corticomedullary gradient**. * Contained within the interstitial space. * Gradient increases in magnitude along the length of the loop. * Papillary tip osmolarity between 600 - 1,200 mOsm/kg depending on need to conserve water loss. * Osmolarity of luminal fluid follows that of the corticomedullary gradient. * Vital role in urine concentration.

Answer 37

* Permits **water movement into interstitial space** by both **transcellular** and **paracellular** pathways. * Contains **aquaporins**. * **Impermeant to ions.** * Na⁺ and Cl^- remain in the lumen. * Becomes progressively more concentrated as water leaves DTL.

Answer 38

* **Impermeant to water** * No aquaporins * **Permeable to Cl^-** * **Cl^- leaves** * **Na⁺ follows** via **paracellular** pathway * As Cl^- and Na⁺leave the lumen, tubular fluid osmolarity returns back to ~ 300 mOsm/kg.

Answer 39

* _Basolateral_ **Na/K-ATPase** sets up an **Na⁺ gradient**. * Na⁺, Cl^-, and K⁺ ⇒ epithelial via _apical_ **Na/K/2Cl cotransporter (NKCC2)** brings all three ions into epithelia * Uses Na⁺ gradient as driving force * Target for _loop diuretics_ like **furosemide** * Leads to increased urine production and loss of K⁺ (_hypokalemia_) * Na⁺ ⇒ interstitial space via _basolateral_ **Na/K-ATPase** * Cl^- ⇒ interstitial space via _basolateral_ **Cl^- channel** * K⁺ can either: ⇒ interstitial space via _basolateral_ **K⁺ channel** ⇒ lumen via _apical_ **ROMK** (Renal Outer Medullary K Channel) * Creates **transepithelial potential ~ +7 mV** * Drives Na⁺and K⁺ reabsorption via **paracellular** pathway * Ensures enough luminal [K⁺] to maintain NKCC2 function

Answer 40

* Ca²⁺and Mg²⁺ reabsorption via **paracellular transport** * Driven by **transepithelial potential** * Inhibition of NKCC2 by loop diuretics prevents formation of transepithelial potential * Promotes hypomagnesemia * Ca²⁺can be reabsorbed later in DCT, hypocalcemia is not seen

Answer 41

**Bicarbonate reabsorbed via similar mechanism as PCT.** **No luminal carbonic anhydrase.** Reaborption slower. * TAL secretes **H⁺** into _lumen_ via **Na⁺/H⁺ exchanger (NHE3)** * **H⁺** converts **HCO₃^-** into **H₂CO₃** * **Spontaneous** conversion of **H₂CO₃** to **CO₂ and H₂O** * CO₂ and H₂O easily enters the cell. * Inside, **carbonic anhydrase II** converts **CO₂** back to **H⁺** and **HCO₃^-**. * H⁺ re-enters lumen via **NHE3 Na⁺/H⁺ exchanger** * **HCO₃**^-moved to _interstitial space_ by **Na⁺/HCO₃^- cotransporter**.

Answer 42

Utilizes the **corticomedullary concentration gradient** to **reabsorb water and salt** as filtrate travels through LoH. Gradient **generated by LoH** and **maintained by vasa recta**. ~ 300 mOsm/kg @ cortical end Up to 1,200 mOsm/kg @ medullary end * **Initial osmolarity** of lumen and interstitial space is **300 mOsm/kg.** * **TAL** absorbs **Na⁺** via **NKCC2** transporter. * Basolateral **Na/K-ATPase** _transfers to interstitium_. * **200 mOsm/kg osmotic difference** between lumen and interstitium generated. * **Water leaves** highly permeable **DTL** until **equilibrium** occurs with higher osmolarity in interstitium (at **400 mOsm/kg**). * **ATL and TAL** imperable to water and **not affected**. Process occurs throughout length of TAL and DTL ⇒ **single effect.** * **Fluid entering DTL** from proximal tubule **displaces 400 mOsm/kg fluid** down and around loop. * **Single effect occurs again** generating higher osmolarity at the tip. * Process **continues repeatedly** until osmolarity of tip 700 - 1,200 mOsm/kg based on need to conserve water. **Fluid leaving TAL into DCT more dilute than the fluid entering LoH.**

Answer 43

* Urea comprises ~ half of solutes in deep renal medullary interstitium. * Diffuses poorly due to small polar nature. * Urea transporters faciliate movement across membranes. * Unilateral vs bilateral * Pool of urea in the deep renal medullary interstitium augments the corticomedullary gradient. * Osmolarity would be 600 instead of 1,200 mOsm/kg without urea.

Answer 44

* _Collecting ducts_ **secretes urea** into interstitium of inner medulla via unilateral **UT-As**. * Apical UT-A1 **requires ADH/AVP** to operate * Basolateral UT constiutive * **Urea enters** _tip of LoH_ via unilateral **UT-Bs**. * Urea carried through distal segment and returns to collecting duct. * **Urea recycling** results in accumulation of urea in interstitium at tip of LoH. * Contributes to corticomedullary gradient. * _Vasa recta_ contains **bilateral UT's**. * Urea in vasa recta **equilibrates** with interstitial urea. * Helps maintain osmotic gradient. * Some can be returned to systemic circulation.

Answer 45

Amount of urea excreted vs recycled depends on the body's water conservation needed. * **Decreased water intake:** * ADH/AVP released from posterior pituitary. * ADH ⇒ GPCR ⇒ cAMP ⇒ PKA * Activates apical UT-A1 of collecting duct * Urea recycled, excretion rates minimal. * **Increased water intake:** * ADH/AVP release suppressed * UT-A1 in collecting ducts operate at low levels * Urea excreted in the urine

Answer 46

* Consists of the: * **Distal convoluted tubule (DCT)** * **Connecting tubule (CNT)** * **Cortical collecting ducts (CCD)** * Most of the Na⁺ and water has been reabsorbed from the filtrate at this point. * Actual amount absorbed in the distal nephron much lower than PCT or LoH * **~ 10% filtered Na⁺** * **~ 20% filtered water** * Regulated by **hormones** associated with **Na⁺ and water homeostasis** * Becomes an important point for **modifying water and electrolyte transport** in response to **changing conditions**

Answer 47

* **Impermeant to water** even in the presence of ADH/AVP * Absorbs **~ 5% of filtered Na⁺** * Movement of salts without water causes tubular fluid in DCT to be **hypo-osmolar** to interstitium

Answer 48

* **Na⁺ and Cl^-** from _lumen into cell_ via _apical_ **Na/Cl co-transporter (NCC)** * Site of action for **tiazide diuretics** such as hydrochlorothiazide * **Na⁺** leaves via _basolateral_ **Na/K-ATPase** * **Cl^-** leaves via _basolateral_ **Cl^- channel**

Answer 49

Together the _DCT and CNT_ reabsorbs **~ 8% of filtered Ca²⁺.** * Ca²⁺ crosses the _apical_ _membrane_ via **TRPV5 Ca²⁺ channel.** * Driving force is the _electrochemical gradient for Ca_²⁺ * Ca²⁺ binds to **calbindin** in the _cytosol_ * Maintains the low cytosolic [Ca²⁺] required by cells. * Ca²⁺/calbindin complex translocated to the basolateral membrne. * Ca²⁺ crosses _basolateral_ _membrane_ via either: * **Ca²⁺-ATPase** * **Na/Ca exchanger** **_Transport of Ca²⁺ regulated by PTH._** * When _plasma [Ca²⁺] low_, **PTH released** from parathyroid. * PTH acts via a **GPCR** through both **adenylyl cyclase and phospholipase C.** * Leads to an **increase** in: * **TRPV5 open probability** * Activity of both basolateral **Ca²⁺-ATPase** and **Na/Ca exchanger** * PTH effects _potentiated_ by **Vit D (calcitriol)** * Vit D **increases synthesis** of most (if not all) **proteins involved in Ca²⁺ transport.**

Answer 50

CNT has transport systems similar to both DCT & CCD. * **Na⁺ and Cl^-** enter _apical membrane_ via **NCC**. * **Na⁺** also enters via _apical_ **aldosterone-sensitive epithelial Na⁺ channel (ENaC)** * **Na⁺** leaves via _basolateral_ **Na/K-ATPase** * **Cl^-** leaves via _basolateral_ **Cl^- channel** * **Ca²⁺** handled by similar **PTH-sensitive pathway** seen in DCT * _Apical_ **TRPV5 Ca²⁺ channel** * _Basolateral_ **Ca-ATPase** and **Na/Ca exchanger** * CNT is **permeable to water** in the presence of **ADH/AVP**. * Increases the levels of **aquaporin 2 (AQP2)**

Answer 51

_Three functionally-distinct cell types in the CCD:_ * **_Principal cells_** * Absorbs Na⁺ via ENaC * Secretes K⁺ into lumen * Absorbs water in the presence of ADH/AVP * **_𝛼-intercalated cells_** * Secretes H⁺ * Generates new HCO₃^- * Reabsorbs K⁺ when plasma [K⁺] is very low * **_𝛽-intercalated cells_** * Secretes HCO₃^- * Reabsorbs K⁺ when plasma [K⁺] is very low

Answer 52

* Basolateral Na/K-ATPase sets up Na⁺ gradient * **Na⁺** reabsorbed by _apical_ **ENaC** * Utilizes Na⁺ gradient as driving force * Blocked by **amiloride** * K⁺-sparing diuretic * Na⁺ ⇒ insterstitial space via **Na/K-ATPase** * **Transcellular Na⁺ movement** generates a **large transepithelial potential of ~ -40 mV in the lumen** * Much greater than other sites of the nephron * **Transepithelial potential** provides strong driving force for **paracellular Cl^- movement** lumen ⇒ interstitium. * **𝛽-intercalated cells** reabsorb Cl^- via _apical_ **Cl/HCO₃^- exchanger (Pendrin)**. * 𝛼-intercalated cells do not participate in Cl^- transport * Cl^- ⇒ interstitium via **Cl^- channel**

Answer 53

* **_K⁺ is secreted by principal cells._** * **K⁺** moves _into cell_ from interstitium by **Na/K-ATPase** * Enter _lumen_ via **ROMK channel** * Driving force is K⁺ concentration gradient and negative potential within lumen. * If **Na⁺ reabsorption blocked** in _TAL by loop diurectics_ or _DCT by thiazide diuretics_ * more Na⁺ appears at principal cells * more Na⁺ reabsorbed here * lumen more electronegative facilitating K⁺ loss into lumen ⇒ explains hypokalemia associated with both classes of diuretics * **𝛼-intercalated cells** can _reabsorb_ **K⁺** via _apical_ **H/K-ATPase** by exchange with H⁺ * Normally minimal * Becomes important when plasma [K⁺] very low

Answer 54

Handled in the distal nephron by intercalated cells. * **_𝛼-intercalated cells_** are the major contributor. * **H⁺** _secreted into lumen_ via apical **H⁺-ATPase** and **H/K-ATPase** * **HCO₃^-** ⇒ interstitial space via **Cl/HCO₃^- exchanger (Pendrin class)** * Able to **synthesize** **HCO₃^-** via **carbonic anhydrase** **** * **_𝛽-intercalated cells_** * **HCO₃^-** _secreted into lumen_ via apical **Cl/HCO₃^- exchanger** (**Pendrin**, different than ones found in 𝛼 cells) * **H⁺**⇒ interstitial space via basolatral **H⁺-ATPase** and **H/K-ATPase** The opposing ability of 𝛼 and 𝛽 cells to secrete titratable acid important in acid/base balance.

Answer 55

**Aldosterone regulates Na⁺ recovery by principal cells.** * Aldosterone produced by RAAS system in response to: * Decreased blood pressure * Decreased renal blood flow * Binds to _basolateral_ **mineralocorticoid receptor (MR)** * Ligand/receptor complex translocated to nucleus * Expression of genes for a number of proteins upregulated including: * **ENaC** * **ROMK** * **Na/K-ATPase**

Answer 56

**Water reabsorption by principal cells of CCD regulated by ADH/AVP.** * **Aquaporin 2 (AQP2)** constantly expressed in principal cells * Sequestered in vesicles in the absence of ADH/AVP * _Basolateral membrane_ always contains **AQP3 and AQP4** * However, no transcellular water movement without apical AQP2 * **ADH/AVP** released from _posterior pituitary_ in response to: * **Increase in plasma osmolarity** * **Decrease in circulating blood volume** * Acts via **V₂ vasopressin receptors** * Causes **AQP2** translocation and insertion into _apical membrane_ * **Completes the transcellular pathway for water movement.**

Answer 57

ECF osmolarity determined by [Na⁺]_ECF Approximate the ECF osmolarity using ECF solute content and ECF solute volume: **ECF_osmolarity = ECF_{solute content} / ECF_volume**

Answer 58

Almost all of the ECF solute content is Na⁺ and it's associated anions (Cl^-, HCO₃^-). Estimate ECF volume as: **ECF_volume = (2 x ECF_{Na⁺ content}) / ECF_osmolarity** ECF osmolarity is tightly controlled. **ECF volume varies with Na⁺ content.** Alterations in Na⁺ reabsorption and/or excretion used to maintain a more or less constant ECF volume in the face of varying conditions.

Answer 59

**The volume on the arterial side of the circulation that provides sufficient tissue perfusion for ongoing metabolic and functional needs.** Systems which maintain a constant ECF via alterations in Na⁺ reabsorption/excretion _monitor the effective circulating volume_ rather than ECF itself. _General rule:_ Increased effective circulating volume ⇒ ↓Na⁺ reabsorption and ↑Na⁺ excretion. Decreased effective circulating volume ⇒ ↑Na⁺reabsorption and ↓Na⁺excretion.

Answer 60

Blood volume affects vascular pressure. Baroreceptors used to sense effective circulating volume. 1. **Arterial baroreceptors** * located in carotid sinus and aortic arch * high-pressure baroreceptors * mediate the classic cardiovascular baroreceptor reflex * Increased BP ⇒ increased firing ⇒ inhibition of SNS gas & activation of PNS break 2. **Cardiopulmonary baroreceptors** * located in atria and pulmonary arteries * low-pressure baroreceptors * essentially sense blood volume 3. **Intrarenal baroreceptors** * located in granular cells of the afferent arteriole * play a role in control of renin release by granular cells

Answer 61

_Ensures constant filtration by the proximal tubule in the face of changing GFR._ Proximal tubule reabsorbs essentially a constant fraction of the Na⁺ presented to it to ensure that Na⁺ is not inappropriately reabsorbed with changes in GFR. Controlled via the effects of GFR changes on the Starling forces of the peritubular capillaries which governs fluid reabsorption. Increased GFR leads to increased reabsorption by the peritubular network ensuring a relatively constant Na⁺ reabsorption rate. * **At normal GFR**: * Low P_PC and high π_PC ⇒ net fluid uptake into capillaries. * **Increased GFR:** * More fluid filtered * Peritubular protein content increases ⇒ **increased π_PC** * Hydrostatic pressure in peritubular capillary decreases ⇒ **dec. P_PC** * Net effect is **increased driving force for fluid movement** from _interstitial space ⇒ peritubular capillary_ * **Enhances absorption of fluid and NaCl**

Answer 62

1. **SNS alters renal blood flow and GFR** * Acts via _𝛼₁-adrenergic receptors_ * Mediates **vasoconstriction of afferent and efferent arterioles** * **Na⁺ excretion tends to move in the same direction as GFR** * If GFR falls, tubules absorb proportionally more Na⁺ so Na⁺ excretion falls * However, due to significant amount of autoregulation, GFR changes are minimal under normal conditions. 2. **SNS upregulates Na⁺ transport systems** in the _proximal tubule_ via _𝛼-adrenergic stimulation_ * Increased activity of **apical NHE3 Na⁺/H⁺ exchanger** * Increased activity of **basolateral Na⁺/K⁺-ATPase**

Answer 63

Important role in the RAAS system: Consists of: * **Macula densa** * epithelial cells in the distal end of the TAL of LoH * releases ATP in response to increased tubule NaCl delivery * ATP ⇒ Adenosine ⇒ A₁ purine receptors on afferent arterioles and A2 purine receptors on efferent arterioles * Results in vasoconstriction of afferent arterioles and vasodilation of efferent arterioles ⇒ reduces RBF and GFR * **Granular cells** * located in the afferent arterioles mostly * Renin production and release * **Extraglomerular mesangial cells** * serves as a communication conduit between the macula densa and granular cells

Answer 64

**Major role in controlling Na⁺ reabsorption/excretion and water balance.** * Renin released from granular cells of JGA * Rate-liming step in the RAAS system * Site of regulation * Renin cleaves circulating angiotensinogen ⇒ angiotensin I * Angiotensin I processed by ACE in the lungs ⇒ angiotensin II * Ang II is the biologically-active form of angiotensin

Answer 65

1. **_Sympathetic nervous system_** * **Renal nerve** innervates **afferent arterioles** * Activation of **𝛽₁-adrenergic receptors** on **granular cells** leads to **renin release** * Provides a level of control driven by _changes in systemic vascular pressure_ * Mediated by **high-pressure baroreceptors** * **Drop in systemic BP elicits renin release** * **Increase in systemic BP inhibits renin release** 2. **_Afferent artiole pressure_** * **Granular cells** act as **intrarenal baroreceptors** * **Pressure drop in the afferent arteriole ⇒ increased renin release** 3. **_Macula densa_** * Senses both _tubular flow and tubular NaCl content_ * When **flow/NaCl content too high** ⇒ **ATP released** * Reduces GFR * **Inhibits renin secretion** * When **flow/NaCl content too low** ⇒ **PGE_2,NO,** and other mediators released by **extraglomerular mesangial cells** * Increases GFR * **Increases renin secretion**

Answer 66

**Ang II has multiple effects that alters the ability of the kidney to absorb both water and Na⁺:** 1. **Stimulation of aldosterone production by adrenal cortex** * Aldosterone _increases activity of apical ENaC and basolateral Na_⁺_/K_⁺_-ATPase_ in the _collecting duct_ * Results in **increased Na⁺ reabsorption** 2. **Increases NHE3 and Na/K-ATPase activity in the proximal tubule** * Results in **increased Na⁺ reabsorption** 3. **Stimulates thirst and secretion of AVP/ADH** * Both **increase water reabsorption** 4. **Preferentially vasoconstricts the efferent arterioles** * Increases GFR * Reduces peritubular hydrostatic pressure * Increases peritubular oncotic pressure * Net effect: * **increased Na⁺ and water reabsorption by the PCT** * **increased fluid movement into the peritubular capillaries** * Reduces blood flow to the vasa recta * **stabilizes and deepens the corticomedullary gradient** * **enhances passive Na⁺ reabsorption by the ATL**

Answer 67

Major effect is to **maintain water balance**. Increases **NKCC2 activity in TAL** of LoH. Increases **ENaC activity of principal cells** in collecting ducts. **Promotes Na⁺ reuptake.**

Answer 68

ANP released when **blood volumes get too high**. **Antagonizes actions of RAAS.** Contribution of ANP to overall Na⁺ and water balance is minimal under normal conditions. * Vasodilates afferent arterioles ⇒ increasing GFR * Inhibits Renin and AVP/ADH release * Net result is **increased fluid flow but decreased reabsorption** * Leads to **diuresis and natriuresis**

Answer 69

Synthesized in the **proximal tubule**. **Increases in Na⁺ intake ⇒ increased dopamine production.** Exact mechanism unclear. _Dopamine has several effects:_ 1. **Dilates afferent arterioles** ⇒ **increases RBF and GFR** 2. Causes **removal of NHE3 and Na/K-ATPase** from _proximal tubule_ ⇒ **decreases transcellular absorption**. 3. **Reduces** **expression of Ang II receptors** ⇒ **prevents effects of Ang II** specifically upregulation of NHE3 and Na/K-ATPase in the PT

Answer 70

**[K⁺]_ECF = 3.5 - 4.5 mEq/L** **[K⁺]_ICF = ~ 140 mEq/L** * Concentration gradient is set up by the **Na/K-ATPase**. * Responsible for the **resting membrane potential of cells**. * Small alterations in [K⁺]_ECF can have significant affects on membrane potential and ability to fire action potentials. * Both hypokalemia and hyperkalemia can cause cardiac arrhythmias. * _Two processes_ considered in K⁺ balance: * **Distribution of K⁺ between ECF and ICF** * **Total amount of K⁺ in the body**

Answer 71

Skeletal muscle represents 2/3 of total cell mass and thus **2/3 of total K⁺** **Abnormal leakage of K⁺** from muscle can result in dangerously high levels of [K⁺]_ECF Can occur with **crush injury** or **rhabdomyolysis**.

Answer 72

[K⁺]_ECF = 3.5 - 4.5 mEq/L and [K⁺]_ICF = ~ 140 mEq/L **Majority of K⁺ is within the ICF.** **Movement of small amounts of K⁺** into or out of the ICF can have **significant affects**. Two most important factors influencing distribution of K⁺ are **activity of Na/K-ATPase** and **serum [K⁺]**. Example: 60 kg female with ~ 20 L of ICF and ~ 10 L of ECF [K⁺]_ICF @ 140 mEq/L ⇒ 2,800 mEq [K⁺]_ECF @ 4 mEq/L ⇒ 40 mEq If 2% of total ICF K⁺ content (56 mEq) moved into the ECF, this would increase [K⁺]_ECF to 9.6 mEq/L ⇒ lethal level

Answer 73

Na/K-ATPase pumps K⁺ into the ICF against its concentration gradient. **Na/K-ATPase activity increased** by several factors: **Promotes movement of K⁺ into the ICF** 1. **Increased plasma [K⁺]** 2. **Insulin** (+ glucose sometimes used as a treatment for hyperkalemia) 3. **Epinephrine** via _𝛽₂ adrenergic_ stimulation 4. **Thyroid hormone** 5. **Aldosterone** through _principal cells in collecting ducts_ 6. **Alkalosis** **Na/K-ATPase activity impaired** by several factors: **Inhibits movement of K⁺ into the ICF** 1. **Cardiac glycosides** (i.e. digoxin) 2. **Chronic renal failure** 3. **Congestive heart failure** 4. **Acidosis**

Answer 74

Several factors increase K⁺ movement out of cells and into the ECF: 1. **Exercise** * K⁺ leaves myocytes during membrane depolarization * transient event as Na/K-ATPase moves K⁺ back into cells under normal conditions 2. **Increased serum osmolarity** * _cells shrink increasing intracellular [K⁺]_ * promotes diffusion of K⁺ out of the cell * can be seen with uncontrolled diabetes 3. **Acidosis** * increased extracellular [H⁺] _promotes H⁺ entry_ into cells * results in _subsequent K⁺ loss_ * acts as a **virtual H⁺/K⁺ exchanger** * no such transporter exists * mechanism may involve the stimulatory effects of acidosis on Na/K-ATPase

Answer 75

Movement of K⁺ between ECF/ICF provides _moment-to-moment_ control of plasma [K⁺] **Total body K⁺ content determined by the kidneys** Normal daily intake of K⁺ is **50-150 mEq/day**. K⁺ **readily absorbed** by the GI system in an **unregulated fashion** Equal amount must be excreted to remain in K⁺ balance **90%** excreted via the **kidneys**, **10%** excreted via the **feces** K⁺ balance maintained by adjusting renal reabsorption and excretion of K

Answer 76

* Filtered load of Na⁺ is 30-40x greater than K⁺ * **K⁺ is both absorbed and secreted** * Na⁺ is always reabsorbed * Regulation of K⁺ balance done via **regulation of secretion** * Renal handing of **Na⁺ has a greater effect of handling of K⁺** than K⁺ on Na⁺ * **Major point of K⁺ control** * K⁺ is **freely filtered** into Bowman's space * **~ 90% of K⁺ is reabsorbed by the PCT and TAL of LoH** * **Collecting tubules and collecting ducts** can **reabsorb and/or secrete K⁺** * ~90% of filtered K⁺ has been absorbed by the time filtrate reaches the distal nephron regardless of intake * Location of **fine-tuning** of K⁺ balance to match K⁺ intake

Answer 77

**PCT reabsorbs ~ 70% of filtered K⁺ mostly via paracellular route.** Driven by two mechanisms: 1. _Transcellular Na+ movement_ sets up an **osmotic gradient** * Drives water movement across PCT via paracellular route * Creates **solvent drag** with sweeps K⁺ along with the water * Greater Na⁺ reabsorption ⇒ greater H₂0 movement ⇒ greater K⁺ movement 2. **Transepithelial potential** varies along PCT length becoming **slightly positive at the distal end of PCT** * **Facilitates K⁺ movement via paracellular route** in this region

Answer 78

**TAL reabsorbs ~ 10% of filtered K⁺ via paracellular and transcellular mechanisms.** * **Lumen-positive transepithelial potential** drives K⁺ movement via **paracellular route**. * _Bulk of K⁺ reabsorption_ via **transcellular** route by **NKCC2 cotransporter** * Moves Na⁺, K⁺, and Cl^- across the lumen * K⁺ crosses **basolateral membrane** via: * **K⁺ channel** * **K/Cl cotransporter** * **Luminal ROMK channel** recycles some **K⁺ back into the lumen** * Moves down its concentration gradient * Ensures sufficient _luminal K⁺ to support NKCC2 function_ * If this did not happen, Na⁺ and Cl^- reabsorption would be limited by [K⁺] in the filtrate

Answer 79

Electrolyte disorder characterized by **reduced reabsorption of Na⁺, K⁺, and Cl^-**. One form caused by a **defective ROMK channel**.

Answer 80

**Responsible for secretion of K⁺ in the collecting tubules.** * _Basolateral_ **Na/K-ATPase** moves K⁺ from interstitium into cell and Na⁺ into interstitial space * Creates driving force for K⁺ movement from cell to lumen * Creates driving force for Na⁺ movement from lumen into cell * K⁺ moves down its electrochemical gradient from cell ⇒ lumen via _apical_ **ROMK channel** * _Enhanced_ by **negative transepithelial potential** * **K⁺ channels** present in _both apical and basolateral membranes_ * More K⁺ channels on apical membrane * _Negative transepithelial potential_ **favors K⁺movement from cell into lumen** * Fraction of K⁺ that does cross basolateral membrane moved back into the cell by Na/K-ATPase * _Increased entry of Na⁺_ via **ENac** _stimulates Na/K-ATPase_ * **Increases driving force for K⁺ secretion** * Explains **hypokalemia** seen with use of **loop and thiazide diuretics**

Answer 81

**Responsible for reabsorption of K⁺ in the collecting tubules.** * _Apical_ **H/K-ATPase** pumps K⁺ into cell from lumen and H+ into the lumen * Important in acid-base regulation * K⁺ moves from cell into interstitium via _basolateral_ **K⁺ channels**

Answer 82

**The key regulated step of K⁺ balance is K⁺ secretion by principal cells.** * Three transport processes determine the amount of K⁺ secretion: * **K⁺ influx from interstitial space** by Na/K-ATPase * **K⁺ efflux into lumen** * **K⁺ efflux into insterstitial space** (recycling) **Majority of control centered on the activity of K⁺ channels** Two types of K⁺ channels in the apical membrane of principal cells: **ROMK and BK** Each has a different role and regulated by different mechanism. * _At low dietary K⁺ ⇒ low K⁺ filtered load_ * **Both ROMK and BK channels inactive** * ROMK sequestered in intracellular vesicles * BK channels closed * **Low level of K⁺ secretion** * _At normal K⁺ loads_ * **ROMK channels moved to apical membrane** * BK channels are _still closed_ * **Moderate level of K⁺ secretion** * _At high K⁺ loads_ * **Both ROMK and BK present and active in apical membrane** * **High level of K⁺ excretion**

Answer 83

**↑ plasma [K⁺] ⇒ ↑ K⁺ secretion** * filtered load of K⁺ proportional to plasma concentration [K⁺] * interstitial space [K⁺] essentially the same as plasma [K⁺] * Na/K-ATPase pumping rate dependent on extracellular [K⁺] * important but not dominant controlling factor

Answer 84

**↑ Dietary [K⁺] ⇒ ↑ K⁺secretion** * renal secretion must match dietary intake * kidney adjusts K⁺ excretion to match intake * mechanism unclear, may involve GI peptide hormones

Answer 85

**Aldosterone synthesis and secretion also stimulated by increased plasma [K⁺] independent of Ang II mechanism.** Aldosterone: * **Stimulates ENaC activity** ⇒ increased Na⁺ entry * High Na+ entry **stimulates Na/K-ATPase activity** ⇒ increased K+ entry * Increased intracellular [K⁺] **stimulates ROMK activity** * **Facilitates K⁺ secretion by ROMK** **Spironolactone** and **eplerenone** _block the aldosterone receptor_ ⇒ Reduces K⁺ secretion. Hypoaldosteronism ⇒ hyperkalemia Hyperaldosteronism ⇒ hypokalemia

Answer 86

**Amount of Na⁺ delivery to prinical cells is a major regulator of K⁺ secretion.** * **High [Na⁺]** at the distal nephron **increases Na⁺ entry** via **ENaC** * Leads to **high Na/K-ATPase activity** increasing K⁺entry from interstitium * Elevated intracellular K⁺ **facilitates secretion via ROMK** * Explains hypokalemia seen with **loop and thiazide diuretics** * **Amiloride or triamterene** _blocks ENaC_ ⇒ **reduces K⁺ secretion**

Answer 87

High flow rates ⇒ **decreased luminal [K⁺]** at principal cells. Facilitates K+ secretion. High flow rates ⇒ **increased Na⁺ reabsorption**. Facilitates K+ secretion.

Answer 88

**AVP/ADH has minor effects on K⁺ secretion.** 1. **Increases ENaC conductance** ⇒ provides larger driving force for K⁺ secretion. 2. **Increases apical K⁺ permeability** 3. However, **reduces urine flow** ⇒ reduce K⁺ secretion Most likely the effects of AVP/ADH cancel themselves out.

Answer 89

There are two primary acid-base disorders: **Acidosis** ⇒ gain H⁺ or lose HCO₃^- **Alkalosis** ⇒ lose H⁺ or gain HCO₃^- There are two ways of developing a primary acid-base disorder: **Respiratory and Metabolic** There are two states of responses: **Compensated and Uncompensated**

Answer 90

Describes the relationship between plasma pH and [HCO₃^-] at a various P_CO2 values. **P_CO2 Isopleths**: shows how pH depends on [HCO₃^-] at a constant P_CO2. **Normal buffer line:** shows the total buffering capacity of the system (HCO₃^- and NBB). _Intersection_ of the two curves represents when **both types of buffers are in equilibrium**. We must exist at a point of intersection.

Answer 91

1. **Buffer systems** * chemical buffers found in ECF and ICF * **minimalizes changes in pH until compensation can occur** * does not remove the excess acid or base from the body * **works immediately** as pH changes 2. **Lungs** * respiratory control centers in the brainstem **adjust ventilation rate** * **increases or decreases CO₂ transfer** to the atmosphere * changes can take place very quickly * compensatory response **occurs within minutes** 3. **Kidneys** * can **adjust the amount of H₊ and HCO₃^-** secreted and excreted * involves upregulation of various enzymes and transporters * full renal compensation **may take up to several days** Successful compensation for a primary acid-base distrubance returns the pH close to baseline but normalization may not occur until underlying cause is removed.

Answer 92

A weak acid and it's conjugate base. Relative concentrations determined by the dissociation constant. Changes in pH will affect the acid/conjugate base ratio and vice versa. Explicit relationship given by the Henderson-Hasselbach equation: pH = pK_eq + log ( [A^-]/[HA] )

Answer 93

Two broad categories of buffer systems: 1. **Bicarbonate buffer system (CO₂/HCO₃^-)** * Most important buffer pair in the ECF 2. **Non-bicarbonate buffers in both ECF and ICF** * _Blood_: proteins, H₂PO₄^-/HPO₄^2- * _Interstitial fluid_: H₂PO₄^-/HPO₄^2- * _Intracellular_: proteins, H₂PO₄^-/HPO₄^2-, phosphate constituents of organic compoounds (e.g. ATP)

Answer 94

Extremely important in acid-base physiology due to: * **Abundance of components** * [HCO₃^-]_ECF ~ 24 mM * metabolism provides unlimited CO₂ * **Open system** * components can be added or removed from the body at controlled rates * **Control by the lungs and kidney** ****Buffering in the system **limited by the amount of available HCO₃^-** **Carbonic anhydrase** catalyzes formation of carbonic acid. Using Henry's Law for [CO₂]_dissolved Henderson-Hasselbach equation for the system **pH = 6.1 + log** [**HCO₃^-] / 0.03 P_CO2** pH can be controlled by alternating P_CO2 or [HCO₃^-].

Answer 95

CO₂ + H₂0 ⇔ HCO₃^- + H⁺ + NBB - ⇔ NBBH Bicarb and plasma NBBs "share" added H⁺. Pulls reaction to the right. Renews available bicarb enhancing buffering capacity.

Answer 96

**Kidneys remove H⁺ if there is excess acid.** Most H⁺ secreted as either: **NH₄⁺** Combined with urinary buffers such as phosphate ⇒ **titratable acid** **Kidneys remove HCO₃^- if there is excess base.**

Answer 97

Several portions of the nephron secrete H⁺ into the lumen. * **PCT** (left panel) * via **NHE3 Na⁺/H⁺ exchanger** * **majority of acid secreted** * **TAL** * also via the **NHE3 Na⁺/H⁺ exchanger** * **𝛼-intercalated cells** of the **collecting duct** (right panel) * excrete H⁺ via an **H/K ATPase** or **H⁺-ATPase**

Answer 98

Tubules **reabsorb essentially all filtered HCO₃^-** mainly in the **PCT**. Involves **carbonic anhydrase**. H⁺ released by intracellular H₂CO₃ breakdown combines with filtered HCO₃^- and cycles around. **Does not result in H⁺ secretion.** **No net creation of HCO₃^-** ⇒ only a reclamation process.

Answer 99

H⁺ and HCO₃^-produced from CO₂ by **carbonic anhydrase**. H⁺ **combines with filtered HPO₄^2-**⇒ **excreted** **HCO₃**^-formed enters **blood** via _basolateral_ **Na/HCO₃^-cotransporter** For every H⁺ excreted as a titratable acid or ammonia, a new HCO₃^-is added to the blood. Loss of H⁺ in the urine is equivalent to adding new HCO₃^-to the blood. Loss of HCO₃^-from the body equivalent to adding H⁺ to the blood. Supply of phosphate and other NBBs limited. Ammonia excretion used to excrete large amounts of acid.

Answer 100

Majority of ammonia synthesized in the **proximal tubule** from **glutamine**. Ammonia can enter urine: As lipid-soluble **NH₃** As **NH₄**⁺via **NHE3** where NH₄⁺can substitute for H⁺

Answer 101

**Titratable acid** measured ex vivo via **titration of urine with NaOH** until **pH 7.4** Represents the **amount of H+ excreted combined with urinary buffers**. Ammonia determined via a seperate method.

Answer 102

**During stable acid-base balance:** Net acid secretion = net addition of H⁺ by metabolic processes. Net acid excretion = net HCO₃^- production. Excretion of HCO₃^- represents a loss of base and must be subtracted. **Net acid excretion** (mEq/day) = urinary titratable acid excreted + urinary NH₄⁺ excreted - urinary HCO₃^- excreted. **NAE with normal plasma pH of 7.4 ~ 60-80 mEq/day.** Much higher with acidosis due to increased NH₄⁺ excretion. Much lower or negative with alkalosis due to increased HCO₃^- excretion.

Answer 103

**↑ P_CO2 ⇒ ↓ [HCO₃^-]/P_CO2ratio ⇒ ↓ pH** Caused by **decreased alveolar ventilation** resulting in **CO₂ retention**. (airway obstruction, chest trauma, neuromuscular disease affecting breathing, inadequte mechanical ventilation) Respiratory failure "**closes**" the bicarbonate buffer system because CO₂ cannot leave. Reduces effectiveness of bicarbonate as a buffer. **Uncompensated respiratory acidosis** with P_CO2 40 mmHg → 80 mmHg results in a pH ~ 7.2 and [HCO₃^-] ~ 28 mM. **Compensation** for prolonged respiratory acidosis through **increased renal H⁺ secretion and HCO₃^- reabsorption**. Requires 12-24 hours to become evident and ~5 days for max effect.

Answer 104

**↑ [HCO₃^-]/P_CO2 ratio ⇒ ↑pH** Caused by **increased elimination of CO₂due to hyperventilation**. (general respiratory stimuli e.g. anxiety or fever, mechanical or voluntary hyperventilation, peripheral respiratory stimuli e.g. altitude, pneumonia, CHF) **Uncompensated respiratory alkalosis** with P_CO2 40 mmHg → 20 mmHg results in pH ~ 7.6 and [HCO₃^-] ~ 20 mM. **Renal compensation** via decreased H⁺ secretion with subsequent drop in HCO₃^- synthesis and increased excretion of filtered HCO₃^-. Brings [HCO₃^-]/P_CO2 ratio back towards normal. Evident within 1-2 hours and max effect in 24-48 hours.

Answer 105

**Anion gap = [Na⁺] - ( [Cl^-] + [HCO₃^-] )** Cations must equal anions. **[Cl^-] + [HCO₃^-] ≠ [Na⁺]** Due to unmeasured anions (proteins and organic acids) **Normal anion gap ~ 9-16.** Greater than normal anion gap means an unmeasured anion is elevated.

Answer 106

**Decreased [HCO₃^-]/P_CO2 ratio due to loss of HCO₃^-or excessive production of H⁺.** 1. **Excessive HCO₃^- loss** * Due to GI or renal causes * diarrhea ⇒ reduces ability of GI tract to reabsorb HCO₃^- * failure to secrete enough H⁺ ⇒ incomplete reabsorption or insufficient generation of HCO₃^- * Cl^- levels increase as HCO₃^- levels fall * _Anion gap is normal_ 2. **Increased H⁺ generation** * Excessive production of organic acids such as lactate or ketoacids * Starvation or uncontrolled diabetes * Ingestion of drugs or poisons * Ethanol, ethylene glycol, or aspirin * Cl^- levels do not rise so [Cl^-] + [HCO₃^-] is not constant * _Anion gap is elevated_ **Uncompensated metabolic acidosis** moves down to lower buffer line with pH ~ 7.2 and [HCO₃^-] ~ 16 mM. Initial **respiratory compensation** ↓ P_CO2 by ↑ minute ventilation ⇒ ↑ [HCO₃^-]/P_CO2 ratio. Takes 15-30 minutes, time for ∆ [H⁺] in CSF to affect respiration. If acidosis persists, **renal compensation** ↑ H⁺ secretion ⇒ ↑reabsorption/synthesis HCO₃^- ⇒ ↑ [HCO₃^-]/P_CO2 ratio.

Answer 107

**↑ [HCO₃^-]/P_CO2 ratio ⇒ ↑pH** * **Due to bicarbonate gain** * administration of bicarb or precursor at rate that exceeds elimination * **Due to net H⁺ loss** * vomiting and loss of HCl from GI * loop diuretics or thiazide diuretics causing ↑ renal H⁺ secretion **Uncompensated metabolic alkalosis** moves buffer line up with pH ~ 7.5 and [HCO₃^-] ~ 30 mM. **Respiratory compensation** ↑P_CO2 by ↓ ventilation ⇒ ↓ [HCO₃^-]/P_CO2 ratio. Limited by respiratory drive due to hypoxemia and hypercapnia.

Answer 108

Overall goal of compensation to return [HCO₃^-]/P_CO2 ratio back to normal (~20).

Answer 109

**P_CO2 = {(1.5 x [HCO3-]) + 8} ± 2** **Used to predict the degree of respiratory compensation in metabolic acidosis.** Measured P_CO2 within calculated range ⇒ adequate respiratory compensation has taken place. Measured P_CO2 outside of range ⇒ concomitant respiratory acid-base disorder also present. P_CO2 \> calculated value ⇒ respiratory acidosis. P_CO2 \< calculated value ⇒ respiratory alkalosis. Rule of thumb: **If there is adequate respiratory compensation, P_CO2 ≈ last 2 digits of pH.**

Answer 110

**P_CO2 = (0.7 x [HCO₃^-]) + 20** Designed to analyze respiratory compensation of metabolic alkalosis. Infrequently used.

Answer 111

**Continence** ⇒ urine storage. Bladder acts as a **reservoir.** **Micturition** ⇒ periodic elimination of urine. Bladder neck, urethra, and urethral sphincter acts as an **outlet.**

Answer 112

_Peripheral nervous system_ regulation of LUT coordinated by **Pontine Micturition Center** and **Pontine Storage Center** Both located in the _rostal pons_. * **Parasympathetic** innervation of LUT via **pelvic splanchnic nerves** * originates in the _sacral spinal cord_ * **Sympathetic** innervation of the LUT via **hypogastric nerves** * originates in the _thoracolumbar spinal cord_ * **Somatic** innervation of the _external urethral sphincter_ via **pudendal nerves** * originates in the _sacral spinal cord_

Answer 113

* _Bladder wall_ is composed of **detrusor smooth muscle** * _Innermost lining_ of the bladder is the **urothelium** * important _protective barrier_ * prevents exposure of bladder musculature and CT to urine * Bladder has _two functional regions:_ * **_Body (fundus)_** * top 2/3 of bladder * _storage chamber_ * _pump for urine expulsion_ * densely innervated by _parasympathetic nerves_ * sparsely innervated by sympathetic nerves * **_Base_** * lower 1/3 of bladder * functions as a _funnel_ * comprised of _two subsections_: * **_Trigone_** * posterior, lower region * bordered by the ureter entrance points (_ureterovesical junction_) and the _urethral orifice_ * **_Neck_** * funnel-shaped extension of the bladder * _connects with the urethra_ * wall composed of an outer longitudinal and inner circular layer of smooth muscle * richly innervated by _sympathetic nerves_ * posseses mainly _𝛼₁ receptors_

Answer 114

1. **Flap-like valve** separates the ureters from the bladder 2. **Anatomical arrangement** of the ureters entrance into the bladder * ureters pass **obliquely** through bladder wall * **bladder smooth muscle contraction compresses the ureters** * prevents retrograde flow during micturition * peristaltic contraction of ureters during urine movement creates a pressure wave which opens entrance

Answer 115

* Abormality often seen in children * Causes: * congeital abnormality * short intravesical ureter * reflux may resolve with age * urinary tract infections * if ureters become inflamed * may lead to pyelonephritis and renal scarring

Answer 116

* only 3-4 cm long * **Smooth muscle** throughout entire length * **inner longitudinal** * important for **urethral shortening and funneling** during micturation * **outer circular** * aid in **sphincteric mechanism** * **Mucus-secreting glands** throughout

Answer 117

* Classified into 4 regions: 1. **Preprostatic urethra** 2. **Prostatic urethra** 3. **Membranous urethra** 4. **Penile urethra** * 18-20 cm long * **Smooth muscle** throughout entire length * **inner longitudinal** * important for **urethral shortening and funneling** during micturation * **outer circular** * aid in **sphincteric mechanism** * Thickened ring of smooth muscle within the _preprostatic urethra_ ⇒ **lissosphincter** * **Mucus-secreting glands** throughout

Answer 118

* Ring of **smooth muscle** * Innervation: * _Parasympathetic_ ⇒ **pelvic splanchnic nerves** * _Sympathetic_ ⇒ _hypogastric nerves_ * Sympathetic control most significant

Answer 119

* Composed of **striated muscle** * Innervated by the **somatic nervous system** * Motor neuron's originate in **Onuf's nucleus** * Traverse the **pudenal nerve** * Allows **voluntary excretion of urine**

Answer 120

**Parasympathetic Innervation** _Stimulates detrusor contraction._ * Body mostly innervated by **M₂ and M₃ receptors** * M₂ receptors more abundant * M₃ receptors most significant * **M₃** mediates the **majority of bladder contraction** * functions via **IP₃-gated Ca²⁺ channels** * release of **intracellular Ca²⁺** results in **activation of MLC kinase** ⇒ contraction **Sympathetic Innervation** _Inhibits bladder contraction._ * Body also has **𝛽2 and 𝛽3 adrenergic receptors** * Binding of **NE** results in detrusor reflaxation * Via stimulation of **adenylyl clycase ⇒ cAMP** * **Facilitates urine storage**

Answer 121

Richly innervated by **sympathetic nervous system**. _Thoracolumbar spine ⇒ hypogastric nerves_. * Abundant **𝛼₁ receptors** * Binding of **NE** stimulates **contraction of bladder neck** * Via **IP₃/DAG pathway**

Answer 122

**_Internal Urethral Sphincter_** **Sympathetic innvervation** Hypogastric nerve ⇒ NE ⇒ **𝛼1 receptors** ⇒ **IP₃** ⇒ Ca²⁺ ⇒ contraction **_External Urethral Sphincter_** **Somatic Innervation** Pudenal nerve ⇒ **Ach** at NMJ ⇒ **nicotinic receptors** ⇒ Ca²⁺ ⇒ contraction

Answer 123

LUT afferent axons found in the: Pelvic splanchnic nerve Hypogastric nerve Pudenal nerve **Pelvic splanchnic nerves** most important. Relays information about **bladder filling** and **noxious stimuli**.

Answer 124

Proper functioning of LUT relies on **reciprocal relationship** between **bladder and urethral activity**. 1. **_Storage_** * **bladder body contractility low** * SNS relaxation * **outlet resistance high** * SNS contraction of bladder neck and urethra * **somatic contraction** of **EUS** * little change in intravesical pressure between 100 and 400 mls 2. **_Micturition_** * **bladder body contractility high** * PNS ⇒ muscarinic receptors ⇒ relaxation * **outlet resistance low** * inhibition of somatic and sympathetic systems * PNS ⇒ NO ⇒ relaxation * Relies on **spino-bulbo-spinal reflexes** from _rostral pons_ * Voluntary control via supra-pontine regions of brain to micturition control center

Answer 125

**Lack of coordination of bladder and urethral sphincter activity.** * Bladder contraction against a closed sphincter * Interferes with bladder emptying * Often seen with **spinal cord injury above S4** * descending inhibition of **bladder-to-EUS spinal storage reflex interrupted** * Bladder may develop **hyperreflexia** * frequent, high pressure contractions

Answer 126

Primarily involves **spinal reflexes**. Pontine Storage Center can modulate them. * **Afferent Pathway** * Low level of afferents via pelvic splanchic nerve * In response to minimal bladder stretch * Compliance & passive properties of bladder smooth muscle * **Efferent Pathways** * EUS contraction via pudendal nerve * IUR contraction via SNS * Inhibition of detrusor muscle contraction via SNS * PNS to detrusor inactive

Answer 127

Increased external urethral sphincter activity in response to an increase in intravesical pressure.

Answer 128

When **micturition threshold** reached, LUT switches from **storage phase to voiding phase**. Voiding can be consciously controlled via cortical input to micturition center. Fluid flow through urethra reflexively causes detrusor contraction and EUS relaxation. * **Afferent pathways:** * High levels of vesical afferent activity via pelvic splanchnic nerve * Due to higher levels of bladder stretch * **Efferent pathways:** * Inhibition of EUS * Inhibition of SNS ⇒ bladder and urethra * Activation of PNS ⇒ bladder and urethra **Results in relaxation of urethral sphincters & contraction of bladder.** Bladder pressure increases leading to urine flow. Modulation by cerebral cortex permits voluntary voiding.

Answer 129

* **At 100-150 ml:** * Activation of **stretch receptors** in bladder wall * Impulses sent to sacral spinal cord * **Spinobulbospinal reflex stimulated** * **First sensation of bladder filling** * **At 150-300 ml:** * **Bladder contracts and IUS relaxes** through end of reflex arc * **Cortex** senses _urge to void & proper location_ * Can allow voluntary EUS relaxation and excretion * **At 400 ml:** * **Intravesical pressure increases sharply** * Partially due to reflex contractions of detrusor * **At 700 ml:** * Pain develops * **Loss of sphincter control**

Renal Flashcards

(161 cards)