Renal Medicine REN

• Role of the kidney, lower urinary tract

The kidneys have 4 main roles.

• Elimination of the endogenous (produced by body) and exogenous (e.g food from outside body) compounds 

• Maintenance of chemical homeostasis, pH regulation.

• Maintenance of volume status such as water content 

• Endocrine signalling – Vitamin D, Erythropoietin

The lower urinary tract (bladder and urethra) has 3 main roles:

• Storage of urine by the bladder

• Urination

• Maintenance of continence (preventing urination) which involves the pelvic floor muscles

Respiratory

• Regulation of pH - respiratory and metabolic acidosis/alkalosis

• Joint metabolic pathways for the regulation of Renin/Angiotensin system 

Cardiovascular

• Maintenace of BP through regulation of Vol + filling pressure during systole/diastole

• Regulate tight ionic concentration needed for cardiac muscle function

• Regulation of Vol required for vascular filliing - adapt to hypovolaemic shock

• Kidney receive afferent innervation (mostly from SNS) and efferent nerves which control blood flow in the kidney

  • Target for new clinical Rx of HTN - Renal denervation

• Autonomic innervation of bladder & urethra are essential for controlling the storage of urine and micturation

• Through Renin-angiotensin system (RAS) - regulates the secretion of aldosterone from adrenal cortex > regulation of Na+, K+ and water

• Regulates Vit D > regulates Ca2+

• Renal tubles is targeted by central hormones vasopressin / ADH

• Kidney is commonly affected by Diabetes > CKD > death

  • DM & HTN are commonest causes of CKD/ESRF

• GI deals with input whilst kidney deals with output - Equilibrium lies in the balance between the 2 systems

• Gut is a rapid source of K+, H+, HCO3- loss

  • H+ loss by vomiting, HCO3- by diarrhoea

  • If gut has significant fluid intake > low Na > oedema so kindey need to increase output to balance it

• Hepatic failure > hypoalbuminaemia > large changes in renal fluid handling > fluid accumulation e.g. ascites

  • Usually kidneys dont filter out albumin but in CKD, albumin can leak out > low levels

• Through production of EPO hormone > regulation of erythrocytes production

• Haem malignancies (myeloma / leukaemia) > deposition of Ab > renal disease e.g. chronic/acute glomeruli nephritis

MSK system

• Crush injury > muscle damage > increased myoglobin & K+ > need urgent renal action as high K+ can affect heart

• Damage to pelvic floor muscles > impacts continence

• Skeletal muscles controls external urethral sphincter

Health services / disbility

• CKD / ESRF > dialysis > increase care needs > cost

• Uraemia > mood changes

Learning outcomes:

• Describe location & topographical relationship of kindey

• Describe the principal anatomical features of the kindey

• Course & relationship of the ureters

• Compare urinary system anatomy in male & female

• Relate the anatomy of urinary system to clinical scenario

Acland’s videos

5.2.27 Kidneys: https://aclandanatomy.com/M

ultimediaPlayer.aspx?multimediaId=10528651

5.2.29 Ureter: https://aclandanatomy.com/Mu

ltimediaPlayer.aspx?multimediaId=10528659

5.2.30 Bladder (M): https://aclandanatomy.com/MultimediaPlayer.aspx?multimediaId=10528655

5.2.31 Bladder (F): https://aclandanatomy.co

m/MultimediaPlayer.aspx?multimediaId=10528661

5.2.32 Review of Urinary System: https://acla

ndanatomy.com/MultimediaPlayer.aspx?multimediaId=1052865

• Extends between the T12-L3 vertebrae - Moves with respiration, hilum (where blood vesssels pass through) at L1 and R kidney at lower level due to liver

• Retroperitoneal, located postero-laterally in front of the posterior abdominal wall

• Structure that pass through the hilum - Renal vein, renal artery and pelvis of ureter

Anterior relations:

• Both kidneys superiorly have suprarenal area & inferiorly have colic & jejunal area

• Right has hepatic area while left have gastric, splenic & pancreatic area

Posterior relations:

• Diaphragm - rests over upper 3rd of each kidney

• Ribs - 12th rib passes posteriorly over upper pole, aswell as 11th rib (left kidney)

• Muscles - kidneys located anterior to medial aspect of the psoas major & lateral aspect of quadratus lumborum & transversus abdominis

• Nerves - subcostal, iliohypogastric and ilioinguinal nerves are related to the posterior surface

• Artery - 12th subcostal artery

Renal cortex & medulla (pyramid)

• Renal paranchyma is made of outer cortex and inner medulla. The cortex extends into the medulla > divides into triangular shaped renal pyramids

• The renal pyramid is the main unit of medulla - contains nephrons (functional unit). The apex of the renal pyramid (renal papilla) opens into minor calyx

Minor & major calyx (calices)

• Minor calyces merge to form major > drains into renal pelvis > ureter

Renal pelvis

• Funnel shaped structure, connetcs to ureter & carries urine to the bladder

Renal columns

• Extensions of renal cortex which separate renal pyramids from each other

Renal hilum

• Deep fissure int he medial margin of both kidney - act as gateway for renal vessels & ureter

Blood supply to the kidneys

• Renal arteries and veins

Nerve supply to the kidneys

• Vasomotor (control of blood vessels) innervation by the sympathetic nervous system

Lymphatic drainage

• Conducted by the lumbar (aka para-aortic) lymph nodes

• Ureteropelvic Junction - ureter connects to the renal pelvis

• Iliac vessel crossover - ureter crosses over the bifurcation of the common iliac artery (at the level of pelvic brim)

• Ureterovesical junction (narrowest)- ureter connects to the urinary bladder

> These narrowing increase risk of renal stones getting trapped & obstruct the ureter

> Urethral obstruction can be lifethreatening as it can increase intrarenal pressure > kidney failure. Nephrostomy is used to drain the kindney directly in this case

• Retroperitoneal in the abdomen & extraperitoneal in the pelvis

• Begin at the level of L2 vertebrae and are slightly lower on the right side

• Run anterior to Psoas major along the transverse process of lumbar vertebrae > cross the pelvic brim at bifurcation of CIA > turn medially at ischial spine

• In females, the ureters pass posterior to the ovaries and fallopian tubes, and lateral to the uterus

• In males, the ureters pass posterior to the vas deferens and anterior to the seminal vesicles

• Initiated by pacemaker cells in the renal pelvis

• Parasympathetic nervous system stimulation controls peristalsis through the vagus nerve and the S2,S3,S4 nerves

• Anterior: space of Retzius which separates it from the anterior abdominal wall

• Posterior: Bordered by the rectum and the rectovesical pouch in males and the uterus and vesicouterine pouch in females

• Inferior: Obturator internus, levator ani muscles and the prostate

• Superior: Peritoneum

• Lateral: Ischioanal fossa

• In adults, empty bladder is in true pelvis, when full (400-500ml), enters greater pelvis

• Location - extraperiotoneal = only superior surface is covered by parietal peritoneum

• Lies behind pubic symphysis separated by retropubic space of Retzius

• Related to Uterovesical pouch in females: Fold of peritoneum creates a space between the bladder and uterus in the female pelvic region 

• Rectovesical pouch in males: Fold of peritoneum creates a space between the rectum and bladder in the male

• Trigone: a smooth triangular area at the base of the bladder, located near the junction of the urethra and bladder. 

• Detrusor muscles: Smooth muscles which make up the bladder wall and is responsible for the bladder's ability to expand to store and release urine.

Pouch of douglas - its the most dependent part of peritoneal cavity in upright position

Blood supply

• By Vesical arteries.

• Vesical venous plexus drains the bladder > internal iliac veins

Nerve supply

• Sympathetic innervation by the T11-L2 nerves allow filling of the bladder by relaxing the detruser muscle  

• Parasympathetic innervation by the S2,S3,S4 nerves allow emptying of the bladder by contracting it

Lymphatic drainage

• By the internal iliac nodes

Male

• 20cm long, has 3 parts - prostatic, membranous & spongy

• Has 2 bends in flaccid state > difficult to catheterise

• Internal urethral sphincter (IUS) - prominent, surrounds internal urethral meatus preventing reflux of seminal fluids

  • Made of smooth muscles, under ANS control

• External urethral sphincter (EUS) - surrounds membranous urethra, made up of striated muscles > allows voluntary contractions. Supplied by pudental nerve (S2-S4)

• Narrowest at EUS & prone to injuries

Female

• 4cm long, straight (easy to catherise)

• IUS - has no anatomical thickening, supplied by ANS

• EUS - more prominent, made of striated muscles > voluntary contractions, supplied by pudental nerve

• More prone to infections

Fluid is a substance that deforms under stress - important fluids are those in which water / fat/lipid are the solvent

• Intracellular compartments (35%): water within cells

• Interstitial compartment (16%): fluid filling the space between cells, amongst the extracellular matrix

• Plasma (blood) (5%): water component of blood ~5L

• Transcellular fluid (2%): separated from the extracellular fluid by a membrane (endothelial or epithelial barrier). Tightly regulated e.g. CSF, peritoneal fluid, aqueous humour, synovial fluid

Ingested water reach these compartments via plasma exchange.

• Combining water in all cmpartments - ~42L for 70kg male. Lesser in female & elderly

  • Intracellular 28L, extracellular (plasma 3L, interstitial fluid 10L), trancellular 1L.

• Examples of transcellular compartments:

  • Peritoneal space - can expand e.g ascites, used in peritoneal dialysis

  • CSF - protected by BBB (has tight junction)

  • Pleural cavity (around lungs) & sinovial fluid (around joints)

Volume distribution

• Inject a substance known to distribute in a given compartment, then calculate Vd

  • Vd is the vol of fluid required to contain the total amount of drug in the body at the same conc as that in the plasma.

• Vd = Q/Cp —> (Q = amount of drug, Cp = plasma conc of drug) L/kg.

To measure the vol of plasma, drug that stays in the plasma can be injected.

• Heparin - large molecule > confined to plasma > Vd 3.5L

To measure Vol of extracellular compartment:

• Gentamycin - strong polar mol with no transporters on cell membrane. Plasma + interstitial Vd = 14-28L

To measure total body fluid Vol:

• Ethanol - high water & fat solubility > Vd 38L

Drug like Tetrahydrocannabinol has high fat distribution > 700L (drug like this which distribute outside the plasma e.g fat can’t be used to measure Vd)

-> To measure the total body water, it is important to find a substance that mixes uniformly with water throughout the body - water is used:

• Water is marked using Deuterium (2H) or tritium (3H) hydrogen isotope to replace the normal 1H in water > known vol of this water is injected & allowed to equilibrate.

• Blood sample taken to meausre proportion of normal:deuterated water measured in plasma - this is used to calculate total body volume.

-> Plasma is the fluid component of blood - usually ~55% of blood volume, the rest 45% is blood cells (haematocrit value)

• Intracellular has high concentration of K+

• Extracellular has high concentrations of Na+, Ca2+, Cl-, HCO3-, glucose & high osmolality.

• Plasma also contains about 60g of proptein, mainly albumin

• Only about half of extracellular Ca2+ is present as free ion (biologically active).

• Rest are bound to albumin = change in albumin conc > change in total Ca2+.

• Free Ca2+ is hard to measure - so total Ca2+ is measured but this need to be corrected to account for changes in albumin conc.

  • Important as renal or liver failure > low albumin > low total Ca2+ level as body tries to regulate free Ca2+ concentration.

• Ca2+ corrected = total Ca2+ + 0.020 (40-albumin g/L)

Osmole - measure of number of molecules that a compound dissociate into when disolved in water. Useful for measuring osmotic forces. E.g:

• 100 mmol of NaCl, yields 200 mOsm in solution, because it dissociates into Na+ and Cl-.

• 2.4 mmol of CaCl2 yields 7.2 mOsm in solution, as each molecule dissociates into 1 Ca2+ and 2 Cl- ions.

• 4mmol of glucose yields 4 mOsm in solution, because it does not dissociate.

• Osmolality is the number of osmoles per unit mass of the solvent (Osm.kg-1) - drives osmosis

• Osmolarity is the number of osmoles per unit volume of the solution (Osm.l-1)

In physiological ranges, the differences is very small as density of water is close to 1Kg.L-1 & the diff between vol of solvent & solution is also small.

• Normally, if there is concentration of a substance is different on either side of an interface (semi-permeable membrane), molecules exchage due to diffusion.

• Osmotic pressure = pressure required on the solution side to stop fluid movement when the interface separates it from water = amount of pressure required to oppose osmosis.

• OP is inverse of water potential = if OP is high, water potential is low.

  • Regions of high OP causes water to pull towards it vice versa.

• E.g 2 compartments, separated by semi-permeable membrane (permeable to water not to solutes). If solutes added to L side > increase osmotic pressure on the L > draws more water to L. Eventually it wills top due to increased hight of water by hydrostatic pressure on L balance out the osmotic pressure!

• Isosmotic = 2 solutions share the same osmolality

• Isotonic = applying the solution to cell will not cause new fluid movement

• So it is possible for solution to be isosmotic but not isotonic = solute is able to pass through SP membrane- e.g Urea

  • Urea crosses free through plasma membrane in cells that has urea transporter.

  • An isosmolar solution if applied to cell, will enter the cell & increase intracellular osmotic pressure & encourage water to enter the cell > swelling & rupture = It is not isotonic!

Urea (red) is initially osmotic with another solution containing Ions (white) that cant cross the membrane. Over time, urea will move from R > L & equilibrate. > increase osmotic pressure in L > increase water gradient > water draws into L.

• So if you have solutions that have same osmolality, they dont need to be isotonic if the solute mol can cross the membrane.

• Capillary wall act as barrier to diffusion similar to plasma membrane of the cell = its a semi-permeable membrane

• Net movement of water will be a balance between:

  • Hydrostatic pressure - generated by heart

  • Osmotic pressure - due to substances that can’t cross the capillary membrane

• In blood, most small mol can cross & are in equilibrium.

• So the main OP are due to protein which cant cross easily > osmotic pressure known as oncotic pressure.

Protein - it is unable to cross the capillary membrane

• Dominant protein in blood plasma is albumin

• Changes in its conc > change in oncotic pressure > change in water movement.

• E.g Hypoalbuminaemia can be due to low production (liver disease) or increase loss (renal failure > proteinuria)

  • This > loss of oncotic pressure within circulation > fluid moves out of circulation > tissues > fluid accumulation in compartments > oedema, ascites, pulmonary oedema

  • Mainly critical if cerebral oedema - Rx with high conc of solute e.g. mannitol to rapidly increase fluid movement from brain into plasma.

• A stable sugar alcohol - when injected > increase plasma & extracellular space osmolality > pulls water from the intracellular & trancellular spaces (e.g. CSF)

• It is therefore used to decrease intracranial pressure e.g post ICH

• It is also an osmotic diuretic - able to expel more fluid in the urine.

• Modern use - inhaled for CF Rx

Remember:

• Hydrostatic pressure is the pressure generate from the heart when it pumps

• Osmotic pressure is proportional to the number of solutes (moles) present in the circulation

The Nephron

• Begins with glomerulus (capillary tuft), surrouded by cup-shaped Bowman’s capsule > continues with tubular system (Proximal tubule, descending / ascending loop of henle > distal tubule > collecting duct > ureters > bladder)

-> Combined blood flow to both kidneys is ~1.1 Lmin > renal plasma flow rate of 600ml/min

Note: the line separates the cortex (up) from medulla (down)

Glomerulus is the site of filtration where:

• Semi-permeable membrane separates the cells & plasma in the capillaries from the filtrate which forms in the Bowman’s space (a cavity within bowman’s capsule)

• Filtration is driven by bulk flow rather than diffusion - the forces that drives the flow are:

  1. Hydrostatic pressure (generated by heart ~90mmHg) - in the kidney is (50mmHg) higher than most other capillaries > drives fluids out of the capillaries

  2. Osmotic / oncotic pressure - higher in the capillaries due to protein. Osmotic force increases along the legth of the capillaries

• Total osmotic pressure in the plasma is very high but most of the constituents are of low molecular mass > freely filtered & reach equilibrium between blood & filtrate.

• Its the osmotic pressure of the protein (oncotic pressure) that affects the driving force - proteins are too large to be filtered > remain in capillaries.

  • Osmotic pressure is estimated using Morse equation

• The above forces act in opposite direction but flow still occurs as hydrostatic pressure is greater than osmotic.

• Hydrostatic pressure (generated by the heart) of capillary & Bowman’s space remains constant & doesnt change along the capillary length (afferent > efferent) as its short

• Oncotic pressure of capillary - Initially equal to plasma > increases as the volume of water in the capillaries decreases so concentration of protein increases

• Hydrotatic pressure of the capillary is the force that drives water to leave the capillary while the oncotic pressure of capillary & hydrostatic pressure of Bowman’s space combined forces water in opposite direction.

• Therefore, the net filtration pressure is the difference between between the hydrostatic pressure of capillary and combined hydrostatic pressure of Bowman's Space and Oncotic pressure of capillary.

  • This is always positive, as there is always a net outwards driving force

Peritubular capillaries are located alongside the nephrons

• Once efferent capillary leaves the glomerulus, it enters a portal vein & travels to 2nd capillary bed surrounding loop of Henle.

  • Here the hydrostatic pressure is similar to systemic capillary, while osmotic (oncotic) pressure is much higher = in this region, blood reabsorbs water & nutrients back into blood stream > peritubular capillaries.

• The efferent arterioles act as ‘portal system’ as they take blood from one capillary to another without going to the heart.

• Endothelial cells of the glomerular capillaries (lines them)

• Glomerular Basement Membrane (GBM)

• Epithelial cells of Bowman's capsule

These layers have specialised adaptations:

• Endothelial cells have small transcellular holes (fenestrations) between them - allows plasma to pass through.

  • Also have -vely charged glycocalyx > creates charged barrier, preventing larger proteins from entering Bowman’s capsule

• GBM also has -vely charged proteins e.g collagen which controls movement of substance across it

• Bowman’s capsule has specialised EC called podocytes - forms filtration slits between their pedicels through which filtrate can pass.

Note: above images are helium ion imaging

Dextrins - large chains of sugar molecules.

Their charge & molecular radius can be changed.

• Cationic dextrans - +vely charged

  • Small size molecules freely filtred, as size increases, the fraction filtered decreases

• Neutral detrans - neurally charged

  • 2nd most easily filtred mol. Smaller ones filtred freely, fraction decreases as size increases

• Anionic dextrans - -vely charged

  • Least easily filtered, as size increases, fraction filter decreases

Most proteins at physiological pH e.g albumin are -vely charged = will not cross & are kept in circulation. The toxic large molecules e.g tagged by liver are +vely charged > likely to be filtred out & excreted

Bulk flow (e.g water flows down the river)

• How most substances move through the filtration barrier during ultrafiltration.

• BF is the movement of solutions from an area of high pressure to area of low pressure.

• As the solvent moves, it carries any solutes dissolved in it - referred as ‘solvent drag’ - regardless of conc gradient.

Diffusion

• Movement of a substance from area of high conc to lower conc as a result of Brownian motion.

• The glomerular barrier is not straight & has long distence = diffusion alone cannot explain glomerular filtration.

Moleules filtered out of the glomerulus:

• Water & most molecules <10kDA in size (Na+, Mg2+, Ca2+, K+, Cl-, HCO3-, glucose & urea).

• Larger mol may found esp if they are +vely charged & if the glomeruli is damaged. Mol with mass >100kDA don’t usually pass into the filtrate.

->Note: 10kDA (kilodalton) = 10000g/mol

Filtration fraction is the proportion of the plasma flow that is filtered by the glomerulus.

• Renal plasma flow = vol of blood flow through a kidney/min = 600ml/min

• Glomerular filtration rate (GFR) = ~120ml/min or 180L/day.

  • Each nephron filters about 30-50nl/min.

  • The rest of the nephron’s task is to reabsorb most of the substances that are filtered.

• Hydrostatic pressure (10mmHg) in the Bowman’s space helps to drive the filtrate along the rest of the nephrons

= 20% is filtred, and 80% continues on via efferent ateriole > renal vasculature > renal vein > systemic circulation

Hydrostatic pressure is important for regulating glumerular filtration. (can’t tell the heart do more, so need local regulation)

There are 2 ways to increase glomerular capillary pressure:

1. Afferent arteriole dilation > increase blood flow > increase pressure > increase filtration

2. Efferent arteriole contraction > reduced blood flow out of the capillary bed > increase pressure > increase filtration.

GFR can be reduced by doing the opposite!

Think of it like a water pipe - left side is afferent, right side is efferent, the hole in the middle > leak is the filtration

GFR is the most important measure of renal function

• Measured using substances that are freely filtered in the glomerulus but are neither secreted nor reabsorbed over the length of tubules.

  • Such substance is produced by the body at stready state (creatinine)

• Cr in urine = conc of Cr in the urine x vol of urine produced (24hrs)

• To calculate rate of Cr excretion, above can be divided by time. i.e (conc Cr in urine x urine vol) / time.

• Calculate the amount of Cr being filtered per unit time -> GFR x plasma Cr concentration.

• Since Cr is freely filtered & not reabsorbed, the rate filtered = amount excreted. So the GFR can be calculated using 1. Urine Cr conc, 2. amount of urine produced in particular time period and 3. plasma Cr conc.

This relies on the fact that the rate of Cr production is fairly constant for given person & is correlated with their sex, mass & age.

• At Equilibrium, the rate of Cr production = rate of Cr loss in the kidney -> GFR x Ccr,p.

  • Since Cr is freely filtered & not reabsorbed, its assumed that all Cr produced is filtered -> K = GFR x Ccr,p - this means the GFR is inversely proportional to Ccr,p.

• Equation for eGFR (see pic)

• As one age, nephrons get progressively lost > reduced GFR > increase in Cr level in blood.

• As we age, the muscle mass also reduces > production of Cr reduces so both effects cancels out

• Below equation is for adults and the age dependent term in the numerator implies that the rate of Cr production falls with age > limits longevity

• Glomerulus is a key barrier to protein loss - protein in the urine = glomerular dysfunction

  • Proteinuria is a key feature of renal failure, when severe > nephrotic syndome.

  • Conditions where there is glomerulus dysfunction is called glomerulonephritis

• Congenital Nephrotic syndrome

  • Rare genetic disorder involving glomerular barrier between the podocytes - can be either Nephrin (NPHS1 mutation) or Podocin (NPHS2) mutation

  • This > glomerulus more permeable to plasma proteins > more protein in the urine

Proximal Tubule is part of nephron, located distal to Bowman’s capsule in the renal cortex.

• Proximal convoluted tubule = Early part (1st 60%)

• Proximal straight tubule = distatl 40%

-> The lumen of these tubules have microvilli to increase SA for absorption

• Carries filtrate and the function is reabsorption of ions and water from the filtrate into blood.

• Does it efficiently as its surface area is enchanced by presence of microvilli, forming brush border.

• Primary active transport occurs due to presence of protein pumps on apical (lumen facing filtrate) and basolatral (facing blood) membrane

• 2ndary active transport occurs due to selective distribution of ion channels, exchangers & co-transporters on apical & basolateral membrane.

• There is movement of ions via either:

  • Transcellular (through cells) - substance from filtrate > epithelial cells > blood

  • Paracellular - substance travel between cells via tight junction.

• Na+ movement > osmotic gradient for movement of water trans & paracellularly. (water follows salt)

• PCT is water permeable = most of the filtrate is isotonic with interstitial space = isotonic with plasma -> by the end of the tubule, 70% of the water is reabsorbed.

• Proximal tubule is the site where most of the filtered Na+ get reabsorbed - via paracellular or transcellular pathway

• Transcellular pathway relies on Na+ > epithelial cells at apical membrane > blood at basolateral membrane.

  • Occurs passively due to high Na+ conc in tubules compared to epithelial cells + due to -ve charge on apical membrane

  -> Na+ enters apical membrane by:

  • Na+ co-transporters: couples passive Na+ entry with other substances e.g glucose (SGLT) & AA (SLC transporters) against their conc gradient

  • Na-H exchanger: allows Na+ entry in exchange for K+ efflux.

  -> At the basolateral membrane:

  • Na+ leaves the cell > blood via Na-K ATPase pump which pumps out 3Na+ in exchange for 2K+ in.

  • This pump is imp to maintain low Na+ conc in the cell > absorption of more Na+ at apical membrane

• In addition, the Na/HCO3 co-transporter also allows N+ to leave the cell > blood.

• Na+ movement into the cell > ostmotic gradient for water movement > water moves out of the tubule via both paracellular & transcellular routes

• Enters trancellulary:

  • via aquaporin 1 channels (AQP1) - abundant in PCT > water permeable.

  • This implies that filtrate is ~isotoinc with interstitial space / plasma.

• Flows through paracellularly:

  • Due to net outward hydrostatic & osmotic forces from the filtrate into the cell.

• By the end of the tubule, 70% of the water is reabsorbed.

Note: this pic dipics epithelial cell of tubular membrane - separated from other cell by tight junction. Left side is apical surface facing filtrate, right side is basolateral surface facing cortical intersititial space. To reabsorb something, it goes from left (filtrate) > apical membrane > cell > basolateral membrane > inteterstitial space where it get picked up by capillaries in the cortex > carried back to systemic circulation

• By Transcellular pathway via 2ndary active transport - coupled with Na+ into epithelial cells down its concentration gradient.

• In early proximal tubule, glucose get transported into epithelial cells by low affinity/high capacity SGLT 2 (1 Na+ & 1 Glu mol) - 90% glucose

• In later proximal tubule, filtrate conc of glucose decreases > 2 Na+ & 1 glu transported into epithelial cell by high affinity / low capacity SGLT 1 transporter (against it conc gradient) - 10%

• Once in the epithelial cells, the glucose moves into blood via GLUT1 (late) and GLUT2 (early) transporters - this is passive down its conc gradient

-> SGLT2 inhibitor e.g canagliflozin & dapagliflozin - used to Rx diabetes by inhibiting SGLT 2 > lower transport maximum for glucose > less reabsorbed into blood > more excreated in the urine .

Note - glucose is a freely filtered = conc of glucose in the blood is similar to that of the filtrate.

-> Glucose movement is rate limited - reaches the limit when all SGLT channels are saturated.

• Once Glu level exceeds certain limit, it can no longer be reabsorbed back into blood > excreated & detected in urine. - this is called maximal tubular load for glucose = 380mg/min or 2.1mmol/min.

• Tm = tubular maximum transport = max reabsorption rate.

  • Not usually reached in healthy pt but can be reached with severe hyperglycaemia in pt with DM.

-> Drugs like SGLT2 inhibitor > lower transport maximum > more glucose get excreated in the urine.

• Absorption of AA is smilar to glucose - via transcellular pathway using 2ndary active transport coupled with Na+

• Transport of AA also has transport maximum (Tm)

• Given AA diversity (~20) - uses many different transporters, most are co-transporters that uses Na+ gradient. Few uses H+ gradient instead

• Renal regulation of HCO3 is important for pH regulation - to avoid metabolic acidosis, nearly all the filtered bicarb need to be reabsorbed. - mostly occurs in proximal tubules

• In the filtrate, the HCO3- (25mM) reacts with excess H+ (which enters through N+/H+ exchanger) -> CO2 & H2O

  • catalysed by carbonic anhydrase

• CO2 & H2O enters the epithelial cells passively - once in, the carbonic anhydrase catalyse the reaction to form HCO3- & H+ again

• On the baselateral membrane, Na+/HCO3- co-transporter transports HCO3- along with Na+ into cortical intestitial space

  • This uses the electrochemical gradient of HCO3- to drive the Na+ against its concentration

• The H+ get exchanged out via Na/H+ exchanger on the apical surface to start the process again.

• Mainly acts in proximal tubule - blocks the action of carbonic anhydrase enzymes

• This > inhibit reabsorption of HCO3- > weak diuretic effect as higher conc of HCO3- in the lumen also reduces water & Na+ reabsorption.

• Used to Rx glaucoma & mountain sickness prophylaxis

• Affect the pH of urine > more alkaline due to increased conc of HCO3-

• Also lead to metabolic acidosis due to lack of HCO3- reabsorption back into blood

• Has diuretic effect > increase urge to urinate

• Action depends on A1 (adenosine) receptor antagonism. This leads to:

  • Increased GFR by opposing vasoconstriction of afferent aterioles (usually mediated by adenosine)

  • Inhibit Na+ reabsorption (inihibit Na/H exchanger) > reduced water reabsorption > increase urine vol > diuresis

There is both active + passive transport from filtrate > blood

• Active: Transcellular absorption at apical membrane - relies on anion exchanger (SLC26A6)

  • Exchange Cl- into cell with anion (such as HCO3- or HCOO-).

    • Once in lumen, the anion get neutralised by H+ & get reabsorbed into the cell

• At the basolateral membrane, Cl- leaves via Cl- channels & Cl-/K+ co-transporters.

  • Na+/K+ ATPase pump on BL membrane maintains intracellular K+ for this process.

• Passive: absorption of Na+, HCO3- & water > high conc of Cl- in the lumen > drives passive paracellular absorption of Cl- down the conc gradient in later proximal tubule.

  • Solute drag - along with water due to hydrostatic pressure pushing water out to interstitial space

• Cl- absorption also get driven by solvent drag as H2O get reabsorbed paracellularly. K+ also get reabsorbed at PCT via this mechanism

• Often very little albumin enters the filtrate - when it does, it binds to plasma membrane of tubule cells.

• Albumin then undergoes endocytosis > catabolised into AA constituents to be used in the body.

• Many organic anions like drug metabolites are actively secreted in the proximal tubule (transport it from blood to filtrate) e.g penicillin, p-aminohippuric acid & furosemide

• The organic ions compete with one another for excretion

• Enters the epithelial cells of the nephron on basolateral membrane through organic anion transporters (OAT)

  • Then enters the filtrate through mutidrug resistance associated proteins (MRP) on the luminal membrane

  • This way, drug excretions relies on both the drug within the filtrate + the onces that get active transported from the blood into filtrate. > high conc of drug in the urine

Rate = 140 x (625/1000) x 0.2 = 17.5

The rate at which Na+ enters the efferent arterioles is higher than the rate at which it enters the filtrate. The concentrations of Na+ in efferent arteriole is similar to the concentration in the filtrate.

i - unchanged

ii - unchanged

iii - lower

Decrease - Decrease - Increase - Increase - decreases - increases - increases - decreases

120 / (40/1,000,000) = 3,000,000

(2000 x (2.5/(24x60))) / (86/1000) = 40.37

Stage 3 - Moderate CKD

• Microscopy of kidney tissue showing tubules - packed together, shares interstitial space

• Epithelial cells (blue), cell nuclei (green) and tubule lumen (dark centre)

They differ in function and structure:

1. Descending limb

2. Ascending limb - composed of 2 parts.

   • Thin ascending limb > thick ascending limb

-> They both have different permeabilities to different substances - required for water & solute reabsorption by creating a corticomedullary gradient

-> Key function of thick ascending limb is to create a hyperosmolar (high ion conc) interstitial space in the medulla to drive water loss from the descending limb & cortical collecting duct

• Osmolarity = concentration of solutes within a fluid (high osmolarity = more solutes

• There is an osmolarity gradient within the renal interstitial tissue

• Moving from cortex to tip of medulla (papilla) , the osmolarity increases = intestitial fluid get saltier

  • Cortex osmolarity = 300mosm (similar to blood)

  • Papilla = as high as 1200 mOsm

• This gradient is set by the action of ascending & descending limbs of loop of Henle

• Permeable to water due to presence of aquaporin-1 channels but not to ions

• Action of ascending limb creates high osmolarity in the intestitial fluid > water leaves from descending limb (also from cortical collecting duct) due to osmotic forces.

• This forces draws water from the tubule lumen > tubular cell > interstitial fluid

  • Means the fluid in the descending limb is hyperosmotic (high osmolarity) due to high ion & low water

• Both thick & thin ascending limbs are impermeable to water

• Also movement of ions out of tubules into interstitial fluid

  • In the thin limb - passive movement of Na+ & Cl- out

  • In the thick limb - active movement of high amount of ions out

Movement of ions from the ascending limb has 2 main effects:

1. Increase in osmolarity of the interstitial fluid due to large amounts of Na+ and Cl-. Interstitial fluid > hyperosmolar.

2. Dilution of the tubular fluid due to the loss of ions. (ascending limb is impermeable to water.

Entry of Ions into the tubular cells:

• Ions enter the tubular cell from the lumen at the apical membrane using Na+/K+/2Cl- co-transporter (NKCC2)

  • Activity of NKCC2 is stimulated by ADH - enchances the corticomedullary gradient

• Step 1 - Creating low intracellular Na+ by pumping it out at the basolateral membrane via Na+/K+ pump (3Na+ out with 2 K+ in)

• Step 2 - Na+, K+ & 2Cl- from the lumen enters the tubular cell at the apical membrane via NKCC2 co-transporter

• Step 3 - Some K+ re-enters the tubule lumen at the apical membrane via K+ channels (ROMK) = K+ recycling - to enable this process to continue

Exit of ions from tubular cell > interstitial fluid

• This occurs at basolateral membrane

  • Na+ leaves via Na+/K+ pump (3Na+ out, 2K+ in)

  • Cl- leaves through Cl- channels + Cl-/K+ sympoter

• Due to this movement of ion out of the tubule, the fluid in the lumen that is going to the collecting duct is hypo-osmotic (diluted)

• Loop diuretics act in the thick ascending limb of loop of Henle

• Work by blocking the Na/K/2Cl co-transporter > bocks reabsorption of Na+, Cl-, K+ from tubular lumen into interstial fluid -> distrupt medullary osmotic gradient = reduced water reabsorption

  • Allows for 20% of Na+ within the filtrate to be excreted > decreases the conc gradient needed for water reabsorption in the collecting duct > increase Na+ and urine excretion

• Used in patients with HF & CKD (to increase urine outpuT)

• Side effects - low K+ > cardiac dysarrythmia when given with digoxin, hypovolaemia, mild metabolic alkalosis, low Mg2+ & Ca2+

Involves actions of both ascending & descending limbs - a 2 step mechanism, creates increasing osmolarity from cortex to papilla:

Single effect:

• Thick AL pumps Na+ & Cl- out into intestitial fluid via NKCC2 co-transporter and Na/K pump

• Since ascending limb is impermeable to water, this reduces the osmolarity of tubular fluid (diluted) = interstitial fluid osmolarity increases

• In the descending limb, water moves into interstitial fluid (ion remains in the tubule) > increase osmolarity of the tubular fluid (concentrated as it moves down)

Flow of tubular fluid:

• Fluid coming from proximal tubule to descending limb has osmolarity of ~300mOsm

• This fluid push the exisiting hyperosmolar fluid down into the bend of loop of Henle - the new fluid then loose its water to become hyperosmolar & cycle repeat

• This is the two-step repeating mechanism which push high osmolarity fluid down the descending limb, replaced by lower omolarity fluid = fluid near papilla at the base of descending limb has high osmolarity (concentrated) than the fluid near the cortex.

• In the ascending limb, repeat cycle > more & more Na/Cl pumped out into interstitial fluid to maintain higher osmolarity.

• Result of this gradient > normally there is 200mOsm more osmolarity in fluid at start of descending limb compared to the fluid at the end of ascending limb

Cortex (diluted), medulla (concentrated)

Vasa recta = capillaries that accompany the loop of Henle along its course through the medulla > cortex. They also have ascending & descending parts

• Freely permeable to ions, urea & water (both parts)

• Solutes exit & water enters in the descending limb, solutes enter & water exit ascending limb > 2 effects cancel out > only small change in blood osmolarity.

• Blood entering the descending limb has osmolarity of 300mOsm > peat at 1200 at the bottom of the loop > fall again at the ascending limb - it still collects more Na+ & Cl- so the blood leaving the vasa recta is 325mOsm

• This allows vasa recta to return some ions back into the sytemic circulation - loss of ion is countered by the counter current multiplier mechanism by loop of Henle

• Vasa recta helps maintain (not set up) the corticomedually gradient = process known as countercurrent exchanger mechanism

1. Isotonic fluid enters the descending limb of the loop of Henle

2. Water leaves the descending limb as the walls of the descending limb are permeable to water. Water leaves as the surrounding interstitial space is more concentrated. This makes the fluid in the descending limb more concentrated (Hyperosmotic)

3. Na+ and Cl- leave the ascending limb into the interstitial fluid. This makes the interstitial fluid more hypertonic. However, the ascending limb is impermeable to water loss so water stays in the tubule and the fluid becomes less concentrated (Hypo-osmotic)

4. Concentrated fluid (Hyperosmotic) moves from the descending limb to the less concentrated fluid (hypo-osmotic) in the ascending limb

5. With each cycle, the concentration of the fluid at the tip of the loop (in the medulla) increases. This creates the necessary gradient for the kidney to effectively reabsorb water and concentrate urine

• Na+ absorption also occurs in the distal tubule

• Na+ from filtrate > tubular cell via Na+/Cl- symporters

• Once in the cell, they get transported out into the interstitial fluid via Na/K pump & K/Cl co-transporter

• For this to occur, conc gradient inside the tubular cell of distal tubule must be established.

  • This is created through Na/K+ antiporter on the basolateral membrane which transports 3Na+ out & 2K+ into the tubular cell. > low Na+ conc & high K+ conc inside the tubular cell

• Distal tubule is impermeable to water, so it looses the ion but retains the water > solute becomes diluted (hypo-osm)

E.g Bendroflumethiazide, indapamide (thiazide like)

• Acts in distal tubule > blocks Na/Cl- co-transporter

• Effect as moderate diuretic > excess urine

• Used as antihypertensive med / alongside furosemide for diuresis

• Side effects - increase uric acid, hyperglycaemia, hyponatraemia

• Distal convoluted tubules empty into collecting tubules (CT) which join together to form collecting duct.

• Main cells in the CT are principal cells - reabsorb Na+ from filtrate & secrete K+ into filtrate.

  • This process is tightly regulated by aldosterone - increases Na+ reabsorption & K+ excretion from principal cells

• Aldosterone has both rapid & delayed effect:

  • Rapid - increases activity of ENaC (epithelial Na channels) on apical membrane > more Na+ enters the cell from filtrate (more absorbed)

  • Delayed - it acts through nuclear receptors inside the cell to produce protein that activate Na/K pump on the basolateral membrane > moves Na+ into interstitial fluid & K+ into cell (so that Na+ can conti reabsorbed)

    • Delayed action also stimulates production of more ENaC on apical side

• In the collecting duct, water reabsorption is controlled independently by ADH

• It increases the no of aquaporin channels (AQP2) > making the duct more permeable to water > water enters from the filtrate into cells of CDs

• The water then get transported out into medullary intestitial space via AQP 3 channels

• ADH also increase water reabsorption by contributing to corticomedullary gradient by:

  • increasing activity of Na/K/2Cl co-transporter in thick AL cells > more ions enter the medullary interstitial fluid

  • Selectively increasing the activity of UT-A1 urea transporters in the medullary collecting duct > allows some urea to enter medullary interstitial fluid

• Corticomedullary gradient creates driving force for water reabsorption in the CDs

• Overall, due to water reabsorption in CD, the fluid in the duct becomes concentrated with urea > highly conc urine

• Acts on the collecting tubules and collecting ducts

• Acts by blocking the effect of aldosterone on the CDs > moderate diuretic effect > K+ sparring as aldosterone usually increases secretion of K+ into the filtrate in exchange for Na+

• Used to Rx heart failure

• SE - gynaecomastia, menstrual disorders, testicular atrophy, hyperkalaemia

• Eplerenone is newer more specific mineralocorticoid inhibitor - expensive

-> Amiloride is also a K+ sparring diuretics

Urea cycling

• This occurs in the distal tubule & collecting duct

• This mechanism is ADH dependent - increases when ADH conc increases

1. Late distal tubule & Cortical CD are urea impermeable. ADH > makes them permeable to water > water leaves from tubule to high osmolarity interstitial fluid > high urea conc in the tubule as it cant leave

2. In the medullary CD, ADH increases water efflux + urea efflus via UT-A1 (urea transporter A1) > urea diffuse out of the duct > medullary interstitial space (dependent on high urea conc created by step 1)

3. Urea in the medullary interstitial space > high osmotic pressure in the medulla > kidneys able to reabsorb more water from medulla into medullary interstitial space - contribute to corticomedullary gradient

4. There is a urea contercurrent as some urea that enters medulla diffuse back into loop of Henle going through the nephrone again through UT-A2.

In summary, the recycling of urea between the collecting duct and the loop of Henle further increases the concentration of solutes in the medulla, enhancing water reabsorption

• Tubular fluid osmolality rises as fluid passes down the descending limb of the loop of Henle and reaches its highest level near the loop’s tip.

• It falls after fluid passes through the ascending limb, becoming lower than plasma osmolality.

• As fluid travels down the collecting duct, water is reabsorbed—particularly when ADH is present—so the urine becomes more concentrated and its osmolality rises.

• The initial flow rate is approximately equal to the glomerular filtration rate, about 125 mL/min.

• Flow decreases as water is reabsorbed, especially in the proximal tubule.

• Further water reabsorption occurs in the loop of Henle.

• The amount reabsorbed in the distal tubule and collecting duct depends strongly on ADH: more water reabsorption means lower tubular flow and a smaller urine volume.

• ADH (vasopressin) in the main hormone that regulate urine osmolality & flow. Also can increase BP by constriction of blood vessels.

• ADH is synthesised in neurons in the hypothalamus.

• Their axons travel through the pituitary stalk to the posterior pituitary, where ADH is stored in nerve terminals.

• When these neurons are stimulated, ADH is released from the terminals into the blood by exocytosis.

• ADH is a polypeptide, acts on cells in the distal tubule and collecting duct. > increase expression of AQP2

• It binds to V2 receptors (Gs) on the basolateral membrane, which is accessible from the blood.

• This signalling increases the amount of AQP2 in the apical membrane.

• AQP2 allows water to pass from the tubular fluid into the cell, increasing water reabsorption.

• ADH binds to a basolateral V2 receptor, a Gs-coupled receptor.

  • This activates adenylyl cyclase, increasing intracellular cAMP.

• cAMP activates protein kinase A (PKA), which phosphorylates AQP2 and promotes increased transcription of the AQP2 gene through the cAMP response element.

• Vesicles containing phosphorylated AQP2 then move to and fuse with the apical membrane, increasing its water permeability.

• The rapid effect involves phosphorylation of AQP2 already present in intracellular vesicles and their fusion with the apical membrane. This quickly increases water permeability.

• The slower effect is increased transcription of the AQP2 gene, which leads to greater AQP2 production over time and supports a longer-lasting increase in water reabsorption.

• With little or no ADH, the distal tubule and collecting duct reabsorb relatively little water.

  • A large volume of dilute urine is produced, with low osmolality and high flow.

• With maximal ADH, more AQP2 is inserted into the apical membrane, so more water is reabsorbed.

  • This produces a smaller volume of concentrated urine, with high osmolality and low flow.

• ADH increases the activity and expression of the urea transporter UT-A1 through V2 receptor signalling.

• ADH > V2 receptor on basolateral membrane > activates adenylyl cyclase > increase cAMP > activates PKA > phosphorylation of UT-A1 channels + increased transcription of UT-A1 gene via CRE.

  • Vesicles containing phosphorylated UT-A1 > apical membrane & fuse > allows reabsorption of urea into medullary interstitial space - through urea cycling, this enchances water reabsorption

• This promotes urea movement into the medullary interstitial space. Urea cycling helps maintain the high osmolality of the medulla, which supports water reabsorption from the collecting duct & helps kidney produce concentrated urine.

• Protein starvation > lower amount of urea available.

• Because urea contributes to the high osmolality of the medullary interstitial space, less urea may reduce the medulla’s ability to draw water from the collecting duct.

• This can make it harder for the kidney to reabsorb water and produce concentrated urine.

• Renal medullary cells are exposed to a highly concentrated environment. - Osmolality here is higher than anywhere else in the body ~1200mOsm (other cells may lyse)

• One adaptation is to accumulate organic osmolytes, which raise intracellular osmolality without greatly disrupting cell function. (these are not biologicaly active)

  • Examples include sorbitol, inositol and betaine. This helps protect cells from the effects of the surrounding high osmolality.

• Diabetes insipidus = disorder in which the kidneys cannot conserve enough water to produce concentrated urine.

• In central diabetes insipidus, the problem is insufficient ADH secretion.

• In nephrogenic diabetes insipidus, ADH is present but the kidneys do not respond adequately to it. - often due to problem with V2 receptors

• Without effective ADH action, the collecting duct reabsorbs less water and produces a large volume of dilute urine (polyuria).

• Ongoing water loss can cause dehydration and reduced circulating blood volume (hypovolaemia), stimulating excessive thirst (polydipsia).

• If the patient cannot replace the lost water, plasma sodium may rise, causing hypernatraemia.

• Central diabetes insipidus results from reduced ADH secretion.

• Causes include head injury, tumours and infections.

• Rx - Desmopressin, an ADH analogue, can replace the missing hormone.

• Thiazide diuretics can also be used; despite being diuretics, they may reduce urine volume by promoting water reabsorption in the proximal tubule, protect against hypernatraemia or increase aquaporin expression.

• Nephrogenic diabetes insipidus results from reduced kidney sensitivity to ADH.

• Causes include lithium toxicity, hypercalcaemia and genetic mutations affecting the V2 receptor or AQP2.

• Rx include thiazide diuretics and a low-salt diet, which can help reduce urine output.

• Desmopressin is generally avoided because the kidneys are insensitive to its action.

In nephrogenic diabetes insipidus, the kidneys do not respond normally to ADH, often because of a defect involving the V2 receptor or AQP2. Giving desmopressin is therefore unlikely to restore normal water reabsorption.

• SIADH is excessive or inappropriate ADH secretion.

• ADH increases water reabsorption in the distal nephron, resulting in concentrated urine.

• Retention of water dilutes the sodium in the blood, leading to hyponatraemia.

• Head injury is one cause

• Rx - Fluid restriction reduces the amount of water available to worsen hyponatraemia.

  • Urea can be filtered into the kidney tubule and increase the osmolality of the filtrate, helping retain water in the urine.

  • Aquaretic drugs block ADH action > increase water loss.

• Aquaretic drugs increase water loss while having less effect on salt and ion loss than conventional diuretics.

• They act in the late distal tubule and collecting duct by blocking ADH action at V2 receptors (V2 receptor antagonists).

• Vaptans, such as tolvaptan, are examples.

  • Used to Rx chronic hyponatraemia or SIADH

• In diabetes insipidus, ADH is absent or ineffective, so the kidney reabsorbs too little water.

  • The result is dilute urine, usually with high urine volume and a risk of dehydration and hypernatraemia.

• In SIADH, ADH activity is excessive, so more water is reabsorbed and the urine is concentrated.

  • Water retention can cause hyponatraemia.

• In SIADH, excess ADH causes increased water reabsorption in the distal nephron and collecting duct.

• This concentrates the urine while retaining water in the body, which dilutes plasma sodium and causes hyponatraemia.

• Treatment options include fluid restriction, urea and aquaretic drugs such as tolvaptan.

• The vasa recta are formed when efferent arterioles from the glomeruli > portal vessels > capillaries that descend from the renal cortex deep into the medulla and form hairpin loops.

• They take water and solutes from the interstitial space back into the systemic circulation.

• They can also supply substances to the interstitium, from where they may be secreted by the tubules.

• Permeable to small molecules (except protein) > osmotic pressure in the VR chanfes with the local osmolality

• As a result, VR dilutes the interstitium on descending limb but concentrates it on ascending limb

• The vasa recta run alongside the loop of Henle in a hairpin arrangement, allowing passive exchange between blood and the surrounding interstitial fluid.

• On the descending limb, water leaves the vasa recta and solutes enter, so the blood becomes more concentrated.

• On the ascending limb, water enters the vasa recta and solutes leave, so the blood becomes more dilute.

• This exchange helps limit disruption of the medullary concentration gradient.

• Net movement into the vasa recta is promoted by low hydrostatic pressure and high oncotic pressure within the capillaries.

• The high hydrostatic pressure of the turgid interstitial space also favours movement of fluid into the capillaries.

• Small molecules can cross the capillary walls, while proteins are largely excluded.

• Flow rate in the descending limb declines as water leaves

• Flow rate in the asending limb increases as water arrives

• The net change in FR from the kidneys is relatively small, as on average only 1.25ml.min-1 of urine is produced, and renal flow is 600ml.min-1

There are 2 key mechanisms in the autoregulation of renal blood flow, by regulating diameter of vessels

• Myogenic response - primarily occurs in the afferent arterioles > regulates total renal blood flow.

• Tubuloglomerular feedback - acts at individual nephrons to regulate single nephron GFR. Macula densa cells in the distal tubule sensing tubular salt and influencing the afferent arteriole to adjust single-nephron GFR.

  • If it occurs across many nephrons, it can also affect overall renal blood flow.

• Renal autoregulation does not depend on central neuronal input (i.e spinal cord reflex pathway - responses can occur even when the kidneys are removed from the body and studied ex vivo.

• This supports the idea that the kidney has local mechanisms for adjusting its own blood flow and filtration.

• As BP increases/ decreases, the autoregulation ensure constant flow to ensure stable GFR (which depends on stable blood flow)

• Myogenic reflex only occurs in afferent arterioles

• When perfusion pressure rises, the afferent arteriole wall stretches.

• The smooth muscle responds by contracting, narrowing the vessel and increasing its resistance > reduce flow.

• This limits the rise in renal blood flow and helps prevent GFR from changing sharply as blood pressure changes.

• Reducing arterial diameter can > low pressure inside the vessel - but in reality the perfusion pressure continue to rise (Poiseuille’s law) = only small change in afferent arteriole diameter is needed to correct for changes in pressure within renal vessels.

• Increased pressure stretches the arteriole wall and opens stretch-activated cation channels in its smooth muscle cells.

• Positive ions enter, depolarising the cells > opens voltage-gated calcium channels, allowing more calcium to enter.

• The increased intracellular calcium causes smooth muscle contraction and constriction of the arteriole.

• This response is also known as the Bayliss effect.

• The myogenic response helps stabilise renal blood flow and GFR across a range of pressures.

• It may also reduce the effect of high systolic pressure peaks, to which the response may be particularly sensitive.

• By limiting pressure and flow reaching the glomerulus, it helps protect the fragile glomerular capillaries from damage.

• Tubuloglumerular feedback is the key way in which each nephron can regulate its GFR (keep it constant)

• This depends on Macula densa cells - specialised cells in the epithelial lining of the distal tubule.

• Because the distal tubule passes close to the afferent and efferent arterioles of its glomerulus, the macula densa can signal changes in tubular fluid to the afferent arteriole.

• This allows the nephron to adjust its own GFR.

• A high distal tubular Na+ & Cl- concentration is detected by the macula densa through NKCC2 cotransporters.

• The cells release ATP, which is broken down into adenosine.

• Adenosine causes afferent arteriolar vasoconstriction, reducing glomerular hydrostatic pressure and lowering GFR.

• This mechanism is hence a negative feedback system

• It is negative feedback because an increase in GFR leads to more sodium and chloride reaching the distal tubule.

• The macula densa detects this and signals afferent arteriolar constriction, which reduces glomerular pressure and GFR.

• The response therefore opposes the initial increase.

Caffeine is an adenosine receptors antagonist.

• This reduces adenosine’s vasoconstrictor effect on the afferent arteriole.

• The arteriole therefore constricts less, increasing glomerular hydrostatic pressure and GFR.

In-vivo the renal blood flow is also influenced by:

• Renal innervation

• Circulating hormones

These two factors help match the needs of the body against the wants of the kidneys

• There is dense plexus of nerves innervating & regulating renal vasculature

• Most efferent nerves supplying the kidney are sympathetic and release noradrenaline > renal vasoconstriction.

• Hypotension is a key stimulus for sypathetic innervation

• During hypotension, this reduces renal blood flow (RBF).

• The response helps retain volume and redirects blood towards tissues such as muscles that may have greater short-term needs.

• Kidney also have many sensory (afferent) neurones

• Autoregulation uses local mechanisms within the kidney to keep renal blood flow and GFR relatively stable despite changes in perfusion pressure.

• Sympathetic innervation is an external, body-wide control that can override or oppose autoregulation when the body needs to conserve volume or redistribute blood flow, such as during hypotension.

• Simple way to measure renal plasma flow is using USS doppler to find the velocity of the blood.

• To get an average over a longer period of time (more useful), can measure a compound that is completely removed from plasma & excreated in the urine

  • This is similar approach as measuring GFR using creatinine

• PAH is used because it is almost completely removed from the plasma passing through the kidneys by filtration and tubular secretion, then excreted in the urine.

• Assuming the PAH entering the kidney is recovered in the urine, the rate of PAH entering equals the rate leaving

RPF x CPAH,p = V̇ x CPAH,u formula where:

• RPF = renal plasma flow rate

  CPAH,p = concentration of PAH in the plasma

  CPAH,u = concentration of PAH in the urine

  V̇ = urine flow rate

We can rearrange for RPF:

• Without autoregulation, an increase in systemic blood pressure would tend to increase renal blood flow and GFR; a decrease would tend to reduce them.

• The myogenic response constricts the afferent arteriole when pressure rises, while tubuloglomerular feedback reduces GFR when excessive salt reaches the distal tubule.

• Together these responses keep renal blood flow and GFR more stable.

• Stable renal blood flow and GFR help maintain predictable filtration and renal function despite changes in blood pressure.

• The myogenic response adjusts afferent arteriolar resistance in response to stretch, while tubuloglomerular feedback uses distal tubular salt concentration to adjust the afferent arteriole and stabilise single-nephron GFR

• Describe the histological appearance of the kidney and identify the component parts of the nephron.

• Describe the structure of Juxtaglomerular apparatus.

• Describe the histological layers forming the wall of the ureter.

• Describe the functional histology of the urinary bladder.

• List the different types of epithelia lining the urethra.

• Discuss common clinical correlations related to the histology of urinary system.

• Divided into Renal cortex & Renal medulla

• Cortex - outer layer of the kidney tissue, appears darker as it receives 90% of the blood supply

• Medulla - divided into 10-18 medullary pyramids separated by projections of cortex (renal columns)

  • Apices of pyramid projects towards renal pelvis > open into minor calices via perforated places (area cribrosa)

  • Medulla appears stripped due to presence of vasa recta

• Each renal pyramid + surrounding cortical tissue = renal lobe. This is further divided into renal lobules - each consits of group of nephrons emptying into collecting duct

1. abdominal aorta > Renal artery > kidney at the Hilum

2. It then splits into 5 branches of the segmental arteries supplying 5 different sections of the kidneys 

3. Segmental arteries branch into interlobar arteries > travel between renal pyramids towards the renal cortex 

4. As the Interlobar arteries reach the boundary between the cortex and medulla they then form arcuate arteries 

5. Arcuate arteries > interlobular arteries which extend into the cortex and supply the nephrons (give rise to glomeruli)

6. Interlobular arteries then branch off into afferent arterioles which lead to the glomerulus of each nephron. 

7. Inside the glomerulus the blood is filtered through the glomerular capillaries. 

8. After filtration the blood leaves the glomerulus through the efferent arterioles

It mirrors the arterial system as it is in reverse order:

1. Peritubular Capillaries/Vasa Recta capillaries converge to form venules.

1. The venules merge into the interlobular veins, which run parallel to the interlobular arteries.

2. Interlobular veins drain into the arcuate veins 

3. Arcuate veins drain into the interlobar veins

4. Interlobar veins merge into segmental veins.

5. Finally, the segmental veins unite to form the renal vein, which exits the kidney at the hilum and drains into the inferior vena cava

• Cortex have renal corpuscles which are absent in medulla

• Bulk of the cortex is occupied by proximal & distal convoluted tubules of the cortical labyrinth and the medullary rays which are composed of cortical collecting tubules and pars recta

• Centre of a medullary ray is the collecting duct, travelling towards the papilla.

• Medulla appears striped due to vertical nephrons (tubules, collecting ducts)

-> Nephron is the functional unit of the kidney - made up of 2 parts: Renal corpuscle & the system of renal tubules.

-> There are two types of nephron: Cortical nephrons (short looped) and justamedullary nephrons (long looped)

The nephron parts are:

1. Renal corpuscle - this comprises of the glomerulus and Bowman capsule

2. Proximal convoluted tubule

3. Proximal straight tubule

4. Descending thin limb

5. Ascending thin limb

6. Thick ascending limb

7. Macula densa in final portion of thick ascending limb

8. Distal convoluted tubule

9. Connecting tubule (CT) *CT of juxtamedullary nephron forming an arch

10. Cortical collecting duct

11. Outer medullary collecting duct

12. Inner medullary collecting duct

• Its the main filtering unit of the kidney & the 1st part of the nephron

• Formed by a network of capillaries (glomerulus) enclosed within Bowman’s capsule - gives it a visceral & parietal layer

  • Glomerulus are fenestrated = epithelial cells have pores called fenestrae to allow filtration

  • They lie on the glomerular basement membrane

• Bowman’s space = Space inside the capsule that surrounds the glomeruli

• Bowman’s capsule is double layers with different cell types:

  • Outer parietal layer - simple squamout epithelial cells

  • Inner visceral layer - lined by podocytes with fooot processes touching the capillary wall.

Endothelial cell + basement membrane + podocytes > filtration barrier - selectively allows small molecules to pass into ultrafiltrate but blocks larger molecules

• Gaps between the podocytes are filled by mesangium

• Podocytes wrap around the capillaries > contact with glomerular basement membrane via pedicels

• Mesangium consists of mesangial cells (aka Lacis cells) - located between vessels & have 2 properties:

  • Phagocytose debris

  • Can contract to control the diameter of the vessels > provide structural support

JGA is formed where the distal convoluted tubule meets the afferent arteriole of the renal corpuscle. Comprise of 3 cells:

• Juxtaglomerular cells - lining the distal portion of the afferent arteriole, they secrete renin

• Extra/intra glomerular cells - mesangial cells

• Macula densa cells - closely packed cells in the DCT which monitor osmolarity

Simple cuboidal epithelium

• Proximal CT stains more red, its more eosinophillic as there are more cytoplasmic organelles prominent

• Cells of proximal CT also have microvilli brush border (distal CT lacks this)

Loop of Henle

• Thin parts (T) lined by simple squamous epithelium

• Thick part is lined by simple cuboidal epithelium

-> These cells have few organelles & little to no microvilli and low secretion abilities.

Collecting ducts

-> Can be divided into cortial & medullary parts.

-> They are lined by epithelial cells that get taller as the ducts get larger

• Cortical collecting duct - Simple cuboidal cell

• Medullary tubules/ ducts - simple columnar cells

->There are 2 additional cell types found in collecting ducts:

• Principal cells - pale staining, used for ion transport

• Intercalated cells - dark staining, used for acid-base balance

Ureter is B/L [aired tubular structure that transport urine from renal pelvis into blader. Wall consists of 3 layers:

• Tunica mucosa - lined by transitional cells (urothelium) consisting of ulmbrella shaped cells. These cells protect the ureter from toxic urine substances.

  • Epithelium rests on lamina propria of loose CT containing blood vessels supplying the cells

• Tunica muscularis - consists of 2 layers of smooth muscles - outer circular + inner longitudinal layer

• Tunica adventitia (Serosa) - Outermost layer, consits of CT that surrounds the ureter

• Tunica mucosa - lined by urothelium, resting on a lamina propria. The umbrella cells create an impermeable barrier to prevent the leakage of urine

• Tunica submucosa - highly vascular layer. It contains elastic fibres

• Tunica muscularis - contains the detrusor muscle, a large smooth muscle responsible for bladder emptying

• Tunica adventitia - outermost connective tissue layer

• Tunica mucosa - In females this is lined by stratified squamous cells throughout. In males this is lined by different types of epithelium throughout:

  • Urothelium at the prostatic part

  • Pseudostratified epithelium from membranous part

  • Stratified squamous epithelium at the external urethral orifice

• Tunica submucosa - has cavernous tissue spaces for erectile purposes

• Tunica muscularis - A smooth muscle layer, closer to the external urethral orifice a skeletal instead

• Tunica adventitia/serosa - outermost connective tissue layer