Renal physiology

Question 1

Provide an overview of the glomerulus

Answer 1

Acts as the blood – kidney interface. Plasma is filtered from capillaries into Bowman ’ s capsule before heading off down the nephron.

Question 2

Provide an overview of the proximal convoluted tubule

Answer 2

Where most of the filtered load is

reabsorbed ( 60%).

Question 3

Provide an overview of the loop of Henle and the system running within

Answer 3

concentrate urine because of
the high osmolality of the surrounding medullary interstitium. This
high concentration of solutes is maintained by the countercurrent
multiplier system.

Question 4

Provide an overview of the distal convoluted tubule

Answer 4

fine-tunes ’ solute and water

reabsorption

Question 5

Provide an overview of the collecting system

Answer 5

formed by the convergence of several
nephrons to create a collecting duct. These progressively
amalgamate, as they cross the medulla, until opening into papillary
ducts in the renal pelvis

Question 6

What are the types of nephrons and why are they different?

Answer 6

There are two types of nephrons, those localized to the cortex (superficial) and
those extending into the medulla (juxtaglomerular) , the latter characterized by longer
loops of Henle and additional metabolic activity.

Question 7

List the renal blood supply and which arteries penetrate the medulla

Answer 7

Renal artery, renal sinus, interlobar arteries (occupy the space between the renal pelvis and adjacent cortical tissue) divide at the corticomedullary junction l branching arcuate arteries interlobular arteries (traverse the cortex).
No arteries penetrate the medulla

Question 8

Describe the two capillary beds and pressure gradients

Answer 8

The kidneys are unique for possessing two capillary beds in series. The glomerular capillaries are maintained at the high pressure required for filtration. Peritubular capillaries are low pressure. This arrangement allows for large volumes of fluid to be filtered and reabsorbed.

Question 9

Define Glomerular filtration rate

Answer 9

This refers to the filtrate of plasma crossing the glomerular barrier into the urinary space per unit time across all functioning nephrons
(usually expressed in mL/min).

Question 10

What is the Tubular function

Answer 10

The renal tubules reabsorb 99% of the glomerular filtrate, enabling them to regulate electrolyte excretion and to concentrate or dilute urine, according to physiological circumstances.

Question 11

The production of urine is the result of which three processes within the kidney?

Answer 11

• Glomerular filtration.
• Selective and passive reabsorption within the renal tubules.
• Excretion from the distal nephron into the urinary tract.

Question 12

Describe how Acid – base regulation involves the kidney

Answer 12

The kidneys and lungs work together to maintain an arterial pH of 7.35 – 7.45. The lungs excrete CO 2
. The kidneys: (i) prevent HCO 3
loss; (ii) excrete H + ; and (iii) buffer urinary H + .

Question 13

Describe the Endocrine functions of the kidney ie hormones involved

Answer 13

Renin: produced by specialized cells within the juxtaglomerular apparatus Erythropoietin: produced by the peritubular interstitial fibroblasts
in the outer medulla and deep cortex. The kidneys are also an important site of action of several hormones, e.g. aldosterone (promotes Na + reabsorption), ANP (promotes Na + loss), and ADH (increases distal tubular permeability, allowing urinary concentration).

Question 14

Describe the Autocrine functions of the kidneys

Answer 14

Production of NO, endothelins, prostaglandins, natriuretic peptides.

Question 15

Describe the glomerulus, what it comprises of and the Bowmans capsule

Answer 15

The glomerulus is at the start of the nephron and provides the first step in filtering the blood to form urine. The glomerulus comprises a tuft of specialized capillaries attached to the mesangium, both of which are enclosed in a pouch-like extension of the tubule called Bowman’s capsule. Bowman’s capsule is a pocket of epithelial cells in continuity with the epithelial cells of the proximal convoluted tubule (PCT). Blood is filtered through the capillaries of the glomerulus into Bowman’s capsule, and it can then start its journey down the remainder of the nephron.

Question 16

What does the Bowmans capsule contain

Answer 16

Capillaries, The glomerular basement membrane (GBM), Epithelial cells (podocytes), Mesangial cells.

Question 17

Capillaries: Describe the blood flow, how this can be influenced for regulation and how permability is established .

Answer 17

A knot of capillaries lined by endothelial cells. Blood flows in via the afferent arteriole and out via the efferent arteriole (for a capillary bed to have arterioles on both ends is unique in the circulation). Changes in afferent and efferent arteriolar tone are powerful ways of regulating blood flow and pressure within the glomerulus. The capillary endothelium contains large fenestrae. This renders it considerably more permeable (100x) than most capillary beds. A strong ionic glycocalyx helps with charge selection.

Question 18

Describe the contents of the Glomerular basement layer, its formation and principal function as well as the layers comprising.

Answer 18

The GBM is a non-cellular layer, consisting mainly of glycoproteins (esp.type IV collagen), sialoglycoproteins (e.g. laminin, fibronectin), proteoglycans (e.g. heparin sulfate). It is manufactured mainly by podocytes and is
the principal filtration barrier. On electron microscopy, it consists of three layers: the lamina interna, lamina densa, and lamina externa.

Question 19

What are podocytes, what do they produce, what do interdigital seperations form and what pathology is associated with abnormal podocyte function?

Answer 19

Podocytes are specialized epithelial cells that produce the components of the GBM (under cytokine control). They have specially adapted foot processes (hence the name ‘podocyte’) that possess a contractile apparatus. Interdigitating podocytes are separated from each other on the GBM by ‘slit diaphragms’, which constitute the key mechanical and signalling barrier to filtration. Podocytes produce podocalyxin (a sialoglycoprotein) to form a highly anionic coating that allows charge selectivity. Abnormal podocyte function is considered central to proteinuric nephropathies.

Question 20

What are the types of mesangium, how are they displayed within the extracellular membrane, when are they activated

Answer 20

Mesangium is the remaining structural component of the glomerulus. Mesangial cells have an important regulatory function. Two main types have been identified; most are derived from a smooth muscle lineage (and respond to similar stimuli). These are situated adjacent to the endothelium (within the GBM) and are active in signalling, recruitment of non-resident cells, and maintenance of vascular tone. Other mesangial cells are derived from macrophages and monocytes and possess phagocytic properties. Mesangial cells are embedded in an extracellular matrix containing collagen IV and V, fi bronectin, laminin, and proteoglycans. Mesangial cell activation and proliferation occur in response to immune-mediated glomerular injury.

Question 21

The glomerular filter is composed of what layers

Answer 21

• Charged endothelial glycocalyx.
• Endothelial fenestrations.
• The glomerular basement membrane.
• The inter-podocyte slit diaphragm.

Question 22

Glomerular filter consists of the inter podocyte slit diaphragm, what makes up this, describe its dysfunction, what determines filtration and free filtrations

Answer 22

The inter-podocyte slit diaphragm offers a mesh of interlocking proteins and lipids, including nephrin, podocin, CD2AP, and podocalyxin. Podocyte dysfunction (at the heart of many proteinuric nephropathies) impairs both the slit diaphragm and foot process adhesion.
Filtration is principally determined by molecular size and, to a much lesser extent, by charge. The glomerular barrier is very permeable to water. Substances with a MW <5,000Da are freely filtered (unless albumin-bound in plasma). Larger molecules are partially filtered, with filtration fraction depending on both size and charge. Negatively charged molecules have a lower filtration fraction than similarly sized cationic molecules. Albumin (MW 61kDa) is polyanionic and scarcely filtered under normal circumstances. Approximately 70,000g passes through the glomerulus every 24h, of which just 7g (0.01%) appears in the filtrate (and this is usually reabsorbed further down the nephron).

Question 23

What is GFR dependent on? What will this be determined by?

Answer 23

GFR is dependent on the net hydrostatic and colloid osmotic pressure
gradients between glomerular plasma and the fluid in Bowman’s space.
This will be determined by:
• Renal blood flow (RBF):
• Renal blood flow represents 20 – 25% of cardiac output (1.25L/
min). Two to three million nephrons produce an ultra-filtrate of
plasma (125mL/min or 7 170L/day). Most water and solutes are all
reabsorbed into the tubular epithelium.
• Glomerular structure (filtration surface area and permeability).
• Transglomerular capillary pressure (afferent – efferent tone).
• Plasma oncotic pressure.

Question 24

Define autoregulation

Answer 24

Preserves renal blood flow and GFR despite variations in systolic BP.
Predominantly effected by the afferent arteriole: local stretch receptors
quickly adjust afferent arteriolar tone via a ‘ myogenic reflex ’ .

Question 25

Afferent and arteriolar tone

Answer 25

Controls intra-glomerular pressure and fl ow:
• Increased afferent arteriolar tone (vasoconstriction) leads to reduced
flow and reduced pressure within the glomerulus.
• Increased efferent arteriolar tone (vasoconstriction) leads to reduced
flow and increased pressure within the glomerulus.

Question 26

Tubuloglomerular feedback, describe chlorine delivery and importance of this mechanism

Answer 26

TGF allows tubular flow sensing to change GFR: Cl –
delivery to the juxtaglomerular apparatus is sensed at the macula Densa distal Cl – delivery l afferent arteriolar vasoconstriction ld GFR (mediators include adenosine, adenosine triphosphate, thromboxane, NO, and
A2). The importance (and beauty) of this mechanism can be appreciated if large quantities of Cl – (and thus Na +) are pathologically delivered to the distal tubule (e.g. non-oliguric ATN). Through TGF, d renal blood flow leads to d GFR, safeguarding against profound diuresis and volume
depletion. In other words, TGF basically aims to avoid volume depletion/ overload if GFR up or down .

Question 27

How is the sympathetic nervous system involved in regulation

Answer 27

The sympathetic nervous system (noradrenaline/norepinephrine) is a key mediator of vasoconstriction of the afferent arteriole. Thus,
in systemic hypotension (sympathetic activity), renal blood flow is reduced (allowing blood to be diverted to the brain and heart). Noradrenaline also stimulates production of renin and A2.

Question 28

How is Angiotensin 2 involved

Answer 28

A2, with its potent vasoconstrictive effects at the efferent arteriole (with much weaker vasoconstrictor effects at the afferent arteriole), will assist in the maintenance of GFR ( this is why ACE-I drop REGULATION OF GFR 921
transglomerular capillary pressures). Renin also increases with sodium depletion li A2.

Question 29

What dilators are important and what should be avoided?

Answer 29

Vasodilator prostaglandins (PGE 1 PGE 2 and prostacyclin) are also important ( hence the need to avoid NSAIDs when renal blood flow is compromised)

Question 30

Name other factors

Answer 30

Other factors: endothelins (esp. ET 1) are vasoconstrictors (efferent > afferent). ANP and BNP cause afferent dilatation. NO relaxes both the
afferent and efferent arteriole and increases renal blood flow

Question 31

What role does the Juxtaglomerular apparatus have, what does it consist of, what does it comprise of, where are the cells located, what do they contain, what surrounds the AA, What is tubular Cl- sensed by

Answer 31

• The juxtaglomerular apparatus has a regulatory role. It consists of a specialized area of cells that are intimately related to the distal nephron and to the adjacent afferent and efferent arterioles and glomerulus.
• It comprises the macula densa, extra-glomerular mesangium, and arterioles (the last part of the afferent and the first part of the efferent). The macula densa is situated toward the end of the thick ascending limb of the loop of Henle (i.e. in the distal nephron).
• The cells of the macula densa are closely packed with large nuclei and attached to a basement membrane that is intimately related to the extra-glomerular mesangium. They contain large amounts of NO and cyclo-oxygenase.
• Modified smooth muscle cells, called granular cells, surround the afferent arteriole. ‘ Granular ’ refers to conspicuous cytoplasmic granules containing renin that is ready for exocytosis into the surrounding interstitium. Granular cells have dense sympathetic innervation.
• Tubular Cl – is sensed in the macula densa as part of
tubuloglomerular feedback. This instigates changes
in glomerular blood flow and GFR via arteriolar haemodynamics. Renin release is also controlled by this system, although the exact mechanisms are unclear.

Question 32

Describe the tubular epithelia, what surfaces are exposed where, transporters, junctions and movements

Answer 32

The tubular epithelium is a single cell layer. The cells have a distinct polarity (determined by their cytoskeleton). Their luminal (apical or tubular)
surface is exposed to filtrate and their basolateral surface to interstitial fluid (and capillary beds). Specific transporters are located in the membranes at each of these surfaces. There is a tight junction between cells
near the luminal side. Solute and water movement may be passive via paracellular routes (regulated via the tight junction) or active via transcellular routes (regulated via the membrane transporters). This movement
may be from tubular fluid to blood (reabsorption) or
from blood to tubular fluid (secretion).

Question 33

What happens in the tubles

Answer 33

Reabsorb the majority of the filtrate (mainly the proximal
convoluted tubule (PCT)). Given that 180L of plasma is filtered each day, an enormous amount of reabsorption is required.  Regulate solute and water balance (PCT, loop of Henle (LH), distal tubule (DT), and collecting ducts (CD)). Regulate acid – base balance (DT and CD).

Question 34

Passive transport occurs via

Answer 34

• Simple diffusion down a concentration or charge gradient.
• Carrier-mediated diffusion where a specifi c membrane carrier
assists transport across the cell membrane.
• A specific membrane channel.

Question 35

Active transport refers to

Answer 35

Active transport refers to an ion being moved against a concentration,
or charge, gradient. It requires energy (from enzymatic hydrolysis of
ATP). The most important active transporter is the sodium pump (Na +
K + -ATPase).

Question 36

Describe the Na/K pump

Answer 36

• Transfers three Na + from inside a cell in exchange for two K + (this balance means it moves a net positive charge).
• In the kidney, it is found exclusively at the basolateral (capillary) surface of the tubule and plays a prime role in tubular reabsorption.
• It keeps intracellular Na + concentration very low (10 – 30mmol/L) and K + concentration very high ( 7 150mmol/L).
• Na + will then want to move back into the cell down the
electrochemical gradient that has been created — this occurs either through specific sodium channels or via carrier proteins.
• These carrier proteins provide an opportunity for co-transport of other ions into the cell (e.g. K + and Cl – ) or countertransport out of the cell (e.g. H + and Ca 2+) against concentration, or charge, gradients,
i.e. to take advantage of the movement of Na + .

Question 37

Describe Glomerulo-tubular balance

Answer 37

The process whereby a change ( up or d) in GFR is compensated for by a corresponding change in absorption by the rest of the nephron. This prevents changes in the filtered load having major consequences for solute excretion. For example, the amount of sodium reabsorbed in each nephron segment is, in general, proportional to the amount of sodium delivered to that segment. The mechanisms underlying this are
poorly understood.

Question 38

What is absorbed at the PCT, Is it of constant pathology, describe its average dimensions, and a brief cellular profile

Answer 38

• The PCT reabsorbs the bulk of sodium, chloride, bicarbonate, glucose, amino acids, urate, water ( 7 60%), and low molecular weight proteins (e.g. B 2 microglobulin). Appreciable amounts of Ca 2+ and PO 4
are also reabsorbed here (see Table 13.1).
• It is not homogenous — it consists of two parts, a convoluted (cortical) section and a straight (medullary section).
• The ‘ average ’ PCT is 7 14mm long and offers a large surface area (due to the villous-like arrangement at the apical surface of epithelial cells).
The normal kidney contains around 1,000,000 glomeruli; this equates to a potential surface area for reabsorption of >50m 2
.
• The PCT is rich in mitochondria.
• The PCT is able to reabsorb up to 65% of the 24,000mmol of Na + and
180L of water filtered per day.

Question 39

Describe processes that occur at: Early PCT how is the energy driven, further along the PCT Cl- leaves

Answer 39

• In the early part of the PCT, most sodium is reabsorbed via specific transporters (see Fig. 13.5), coupled with absorption of glucose and
organic molecules.
• A further transporter exchanges Na + with H + ions.
• The energy for these processes comes from the sodium gradient into the cell, itself generated by the Na + K + -ATPase
• The gap junctions between epithelial cells are slightly leaky, so the PCT is highly permeable to water.
• In the early PCT, chloride (an excess is generated when sodium is absorbed with other anions or molecules) is reabsorbed via the paracellular route.
• Further along the PCT, Na + and H + are exchanged, while Cl – is exchanged for another base (e.g. formate, bicarbonate, oxalate) . The base and H + are then reabsorbed, so the net result is reabsorption of NaCl.
• Cl – leaves the cell in exchange for K + or via specific chloride pumps.

Question 40

Action of potassium at PCT

Answer 40

In this area of the nephron, K + is mostly reabsorbed down a concentration
gradient via the paracellular space.

Question 41

How is bicarbonate resorbed at the PCT

Answer 41

The PCT reabsorbs 90% of filtered HCO 3
but does not acidify the urine. HCO 3 reabsorption is accomplished by means of H + secretion. Dissociation of carbonic acid (H 2 CO 3 ) within epithelial cells yields an H +ion that enters the filtrate via the Na + /H + exchanger
in the luminal membrane (see Fig. 13.5). The H + combines with HCO 3 in the filtrate to form carbonic acid, which is rapidly converted to CO 2 and H 2 O by carbonic
anhydrase. This recycling of H + means there is no net acid excretion at this point. CO 2 enters the cell by simple diffusion and is converted back to carbonic acid to start the cycle again. Within the cell, the HCO 3 generated from carbonic acid dissociation leaves via the basolateral surface in exchange for Cl – or in association with Na + .

Question 42

What is the action of calcium at the PCT

Answer 42

Mainly paracellular reabsorption across the tight junction down a concentration (and charge) gradient.

Question 43

What is the action of phosphate at the PCT

Answer 43

Co-transported into the cell along with Na +. 2 Inhibited by PTH — meaning that PTH is phosphaturic.

Question 44

What is the action of Glucose, amino acids at the PCT, What drug is approved

Answer 44

Both are co-transported into the cell along with Na +. The sodium-glucose co-transporter 2 (SGLT2) has become a novel therapeutic target in diabetes (inhibition ld glucose reabsorption l glucose excretion). The SGLT2
inhibitor dapagliflozin (SE: weight loss, dehydration) is approved for use in T2DM.

Question 45

What is the The prime function of the loop of Henle

Answer 45

The prime function of the loop of Henle is to establish a gradient of osmolality in the renal interstitium and 6 the tubular fluid. This allows the concentration of urine to be varied widely.

Question 46

Structure of the LOH: Location in the kidney, limbs, location of important cell layer, blood vessels, shape importance, Exchange mathod, Mitochondrial rich region

Answer 46

• The loop dives deep into the renal medulla and then back out into the cortex.
• It consists of a thin descending limb, a thin ascending limb (in some nephrons), and a thick ascending limb. There are important solute and water permeability differences along the loop.
• The macula densa is found close to the thick
ascending limb.
• Capillaries serving the loop accompany it on its journey. These vasa recta have a bespoke ‘ hairpin ’ arrangement, as a ‘ standard ’ capillary network would simply allow the medullary osmotic gradient to dissipate through equilibration with capillary blood.
• This U-shaped organization allows water loss and solute entry in the descending limb to be offset by water entry and solute loss in the ascending.
• This passive exchange of water and solutes perpetuates the hypertonic extracellular environment of the medulla that is crucial for water homeostasis. It is referred to as ‘ countercurrent exchange ’ .
• The thick ascending limb contains cells rich in mitochondria, enabling the active transport of electrolytes. The reabsorption of Na + , K + , Cl –
Ca 2+ continues in this section of the nephron, and the majority of Mg 2+

Question 47

Na absorption pattern inclusive of passive and active components, exit, additional entry, paracellular resorption.

Answer 47

• The descending limb is impermeable to Na + , but water moves into the interstitium down the osmotic gradient. The result is a high luminal Na + and Cl – concentration.
• Na + reabsorption is passive in the thin ascending limb (Na + and Cl – move into the interstitium down a concentration gradient) and active in the thick ascending limb. The active process is again driven by the
basolateral Na + K + -ATPase (the low intracellular Na + concentration it generates allows Na + entry from the lumen).
• This Na + enters principally through the Na + , K + , Cl –
, Cl – (NKCC) co-transporter, which is unique to this section of the nephron (and the target of loop diuretics)
• Na + then exits the cell on the basolateral side through the Na + K + -ATPase, while Cl – and K + exit through a co-transporter. In addition, K + re-enters the lumen through a luminal K + channel (ROMK channel) — a recycling process that is necessary to prevent K +
availability from becoming a limiting factor for the operation of NKCC.
• This movement of K + back to the lumen also keeps it electrically net positive, which facilitates the passive paracellular reabsorption of Na + (as well as K + , Ca 2+ , NH 4+ , and Mg 2+ ).

Question 48

The loop of Henle: the countercurrent system, function, shape, gradient, limbs and water permability, Na absorption.

Answer 48

Allows the concentration of urine to be varied, according to physiological circumstances.
• The U shape of the loop and its capillary network, the differences in permeability (to Na + and water) between the descending and ascending limbs, and the active reabsorption of Na + in the thick ascending limb all underpin the countercurrent system.
• The system maintains an interstitial osmotic gradient that increases from the renal cortex ( 7 290mOsmol/kg) to the tip of the medulla ( 7 1,200mOsmol/kg).
• The thin and thick ascending limbs are both impermeable to water.
• Despite this water impermeability, Na + is reabsorbed in this segment. This reabsorption of Na + (and Cl –), but not water, leaves the tubular fluid dilute and hypotonic ( l this region is often called the diluting segment).

Question 49

What type of fluid enters the loop, what happens as it progresses down, what happens to its tonicity, Ascending limb, fluid description at distal tuble why does it not remain this way

Answer 49

Isotonic fluid (290mOsmol/kg) enters the loop from the PCT.
 • As it progresses down the descending limb, it encounters medullary interstitial fluid of increasing tonicity (the interstitium is hypertonic because of Na + reabsorption without water in the thick ascending limb).
 • The descending limb is permeable to water (but not Na + ), so water flows out, down an osmotic gradient, into the concentrated milieu of the interstitium.
 • As this occurs, the tubular fluid progressively equilibrates osmotically with its surroundings and becomes more and more hypertonic as the loop descends into the medulla.
 • The effect is to concentrate the luminal fluid so that, at the deepest part of the loop, both the luminal and interstitial osmolality reach up to 1,200mOsmol/kg.
 • In the ascending limb, Na + (and Cl – ) are absorbed (via the NKCC transporter) without water, generating an osmotic gradient of 200mOsmol/kg between lumen and interstitium at any given level.
• By the time the luminal fluid reaches the distal tubule, it is dilute and hypotonic.
• It would remain dilute as it passes through the distal nephron and collecting duct, were it not for the action of vasopressin (ADH)

Question 50

How does ADH influence osm

Answer 50

High plasma osmolalityl ADH release li permeability of collecting
duct to water li urine osmolality (up to 7 1,200mOsmol/kg).
• Low plasma osmolalityl ADH release suppressed ld permeability
of collecting duct to water ld urine osmolality (down to
200mOsmol/kg).

Question 51

Urea action, tubule permability, urea escape, tonicity

Answer 51

Urea also makes an important contribution to the maintenance of a hypertonic medullary interstitium.
• The tubules are relatively impermeable to urea, meaning that a significant amount is delivered to the collecting duct. Then, vasopressin-dependent water reabsorption increases luminal urea concentration further.
• However, the vasopressin-sensitive transporters UT-A1 and UT-A3 allow urea to escape into the medullary interstitium.
• Although some re-enters the luminal fluid or equilibrates with the capillary network, the net result is an increase in interstitial tonicity.

Question 52

What occurs in the distal nephron, how are concentration gradients established

Answer 52

The fine-tuning of solute and water reabsorption occurs in the distal nephron. The distal convoluted tubule (DCT) is impermeable to the passive movement of Na + and Cl and water (vasopressin does not affect water absorption here). This allows large concentration gradients to develop when necessary

Question 53

Describe the path of Na

Answer 53

Sodium 75% of the filtered Na + is reabsorbed in the DCT. The thiazide-sensitive Na + Cl co-transporter (NCCT) is the major route. Further Na + is absorbed by Na + /H + exchange, and additional Cl – by Cl – / HCO 3 exchange. H + and HCO 3 – then combine in the lumen to form CO 2 and H 2 O (the CO 2 can be reabsorbed and recycled). The energy for the action of the NCCT co-transporter is again derived from Na + K + -ATPase, as the resulting electrochemical gradient permits Na + reabsorption into
the cell.

Question 54

Describe the path of Ca, what do thiazides block, what a defect could lead to

Answer 54

Absorbed via a specific epithelial Ca 2+ channel under the influenced of PTH and calcitriol. Thiazide diuretics block the NCCT co-transporter. They also enhance
Ca 2+ absorption (exact mechanisms unknown), reducing calcium excretion in the urine. Hypokalaemia occurs, as there will be an increase in Na + delivery to the collecting ducts and 6 additional uptake via ENaCs. This will increase activity of the basolateral Na + K + -ATPase,
and the resulting intracellular K + will then move into the lumen and be lost in the urine. Defects in the NCCT co-transporter also underlie Gitelmans syndrome

Question 55

Two types of cells found in collecting duct, How permability and concentration are linked

Answer 55

Two cell types are found in the collecting duct. Principal cells are responsible for Na + (and water) reabsorption and K + excretion. Intercalated cells secrete H + ( A -intercalated cells) or HCO 3 ( B -intercalated cells). Changes in permeability of the collecting duct allow concentration of urine under the control of vasopressin (ADH).

Question 56

How does sodium resorption occur in the collecting duct

Answer 56

Sodium Reabsorption from the lumen occurs via a specific Na + transporter, the epithelial sodium channel (ENaC), and it then leaves the cell on the basolateral side via the Na + K +-ATPase. Although only 75% of filtered Na + is reabsorbed here, this is the main site of body Na + regulation. In contrast to Na + reabsorption higher in
the nephron, it is predominantly the electrical, rather than concentration, gradient that drives Na + from the lumen into the cell (as the luminal Na + concentration may be as low as 5mmol/L by this stage of the nephron).
Na + K +-ATPase generates a net negative charge within the cell, and Na + moves down this charge gradient via ENaC into the cell. As the tubular fluid becomes more negatively charged, it favours K + movement into
the lumen.

Question 57

Where does potassium enter and how is the concentration and gradient set

Answer 57

Potassium Enters principal cells on the basolateral side via the Na + K +-ATPase and then move into the lumen (along the favourable charge gradient discussed previously) via specific aldosterone-sensitive K +
channels (aldosterone promotes K + excretion). High urinary flow rates help to maintain low intraluminal K + concentrations, allowing the gradient to persist and the channel to operate. Hence, hypovolaemia can l hyperkalaemia.

Question 58

What 4 peptides can alter sodium resorption, which 2 drugs

Answer 58

• Aldosterone , after binding its mineralocorticoid receptor, increases the number of open ENaC channels, regulating Na + absorption
(and excretion). It also increases the number and activity of the Na + K + -ATPase (it can double the surface area of the basolateral membrane).
• Atrial natriuretic peptide ( ANP ) also acts on ENaC, with i ANP l inactivation of ENaC.
• Na + delivery: d delivery li ENaC activity, thereby reducing Na + loss in the urine (and preventing volume depletion).
• Vasopressin (ADH) may also be important through an increase in ENaC numbers and activity.
• Locally produced PGE 2 decreases ENaC activity.
2 Amiloride and triamterene block ENaC, thus reducing both Na + reabsorption and K + excretion. Spironolactone inhibits the effect of aldosterone on its receptor, with similar effects on Na + and K + .

Question 59

What are the 2 intercalated cells, explain their functions and when there may be a shift

Answer 59

These cells are essential to acid – base homeostasis. There are two functional and morphological types. A-intercalated cells are tall, columnar epithelial cells, containing a luminal H + ATPase that enables them to secrete protons. B-intercalated cells are flatter cells that contain a basolateral H + ATPase and a luminal Cl – HCO 3 exchanger (called pendrin) that enables them to excrete base, The A-intercalated cells transport H + ions out of the cell into the tubular fluid. This is aldosterone-sensitive (aldosterone li H + excretion). H + is generated (along with HCO 3) from the dissociation of carbonic acid via carbonic anhydrase. HCO 3 is then returned to the circulation in exchange for Cl – ions via a different basolateral Cl – HCO 3 co-transporter (called AE1 protein). Metabolic acidosis converts the collecting tubule from a state of HCO 3 secretion to HCO 3 absorption (and 6 H + secretion) that involves a phenotypic shift of B intercalated cells to A-intercalated cells. The role of the kidney in acid – base regulation is further discussed on b In circumstances of severe acidosis or d K +, intercalated cells also express an H + /K + ATPase, similar to that responsible for gastric acid secretion. This allows additional H + secretion in exchange for K + .

Question 60

Where is ADH released, in response to what and what does it act on

Answer 60

Vasopressin, or antidiuretic hormone (ADH), is synthesized in the hypothalamus and released by the posterior pituitary in response to
rising plasma osmolality (sensed by hypothalamic osmoreceptors) and/ or significant hypovolaemia (sensed by arterial baroreceptors and atrial stretch receptors).
Vasopressin acts via V 1 receptors to stimulate thirst and systemic vasoconstriction

Question 61

Functions of vasopressin, V2 receptors, What else it acts on which disease is linked

Answer 61

• Vasopressin binds V 2 receptors located on the basolateral membrane of principal cells in the collecting duct.
• It acts to reabsorb water in the collecting duct and 6 to concentrate the urine.
• The duct becomes more permeable to water by the translocation of specific water channels (aquaporin-2) to the luminal membrane.
• Aquaporin-2 is stored in intracellular vesicles ready for membrane insertion (the basolateral membrane is already water-permeable by virtue of aquaporin-3 and -4).
• The high interstitial osmolality, maintained by the countercurrent system, facilitates easy movement of water.
• Vasopressin also increases the permeability of the collecting duct to urea.
• Defects in aquaporin-2 structure and function underlie X-linked nephrogenic diabetes insipidus.
• Increased intraluminal Ca 2+ concentration interferes with aquaporin-2 membrane insertion. This explains the observation that hypercalcaemia causes defective urinary concentrating ability, polyuria, and dehydration.