Urinary Flashcards
What are the three aspects of regulation by the urinary system?
Control volume- Failure = changes in BP, tissue fluid and cell function; kidneys affect ECF directly and ICF indirectly
Control osmolarity- cell shrinkage and swelling
Control pH- dependent on bicarbonate
What are the functions of the urinary system?
Regulation- control of concentration of key substances in ECF
Excretion- excretes waste products
Endocrine- synthesis of renin, erythropoietin, prostaglandins
Metabolism- active form of Vit D, catabolism of insulin, PTH, calcitonin
What is osmolality?
Number of osmoles of solute per kg of solvent
What is osmolarity?
Number of osmoles of solute per litre of solvent
What does oncotic mean?
Osmotic force due to PROTEINS
What is the normal proportions of ions in the ICF (compared to ECF)?
High K+
Low Na+
Large anionic ions
What is the normal concentrations of ECF (compared to ICF)?
Low K+
High Na+
Cl-
HCO3-
How much of everything is eventually recovered by the kidneys?
o > 99% of filtered water is recovered
o >99% of filtered Na+ and Cl- is recovered
o 100% of Hydrogen Carbonate is recovered
o 100% of Glucose and Amino Acids are recovered
o Just a few waste products not recovered (Urea)
o Some substances are actively secreted (e.g. H+)
How much ECF do the kidneys filter every day?
180L/day
How much urine does a human produce each day?
1.5L urine/day
Broadly what makes up the male urinary system?
2 kidneys, 2 ureters Bladder Prostate Urethra
Broadly what makes up the female urinary system?
2 kidneys,
2 ureters
Bladder
Urethra
Give a brief structural description of the kidneys
The Kidneys are retroperitoneal organs that sit either side of the spine in the abdominal cavity, roughly at the level of T12-L3. The right kidney usually sits slightly lower than the left due to the position of the liver.
The Kidneys have a mobility of ~3cm when you breathe due to their proximity to the diaphragm, and the tops of the kidneys are protected by the 11th and 12th rib
What is found anterior to the left kidney?
Supra renal gland Spleen Stomach Pancreas Left colic flexure Jejunum
What is found posterior to the left kidney?
Diaphragm
11th and 12th ribs
Psoas major
Quadratus lumborum and transversalis abdominis muscles
Sub costal, iliohypogastric and ilioinguinal nerves
What is found anterior to the right kidney?
Suprarenal gland
Liver
Duodenum
Right colic flexure
What is found posterior to the right kidney?
Diaphragm
12th rib (as it is lower)
Psoas major, quadratus lumborum and abdominis muscles
Subcostal, Iliohypogastric and ilioinguinal nerves
What is the macroscopic outline of the kidneys (outside to inside)?
Pararenal fat Renal fascia Perirenal fat Renal capsule Parenchyma- outer cortex, inner medulla, renal pyramids and renal papilla Minor calyx Major calyx Renal pelvis
What is the pararenal fat?
Surrounds everything (including renal fascia) Mainly located in posterio lateral aspect of kidney
What is renal fascia?
Sheath that encloses suprarenal glands and kidneys
What is perirenal fat?
Adipose tissue that surrounds the kidney
What is the renal capsule?
Tough fibrous capsule that surrounds the kidney
What is the renal parenchyma made up of?
Outer cortex, inner medulla, renal pyramids - cortex extends into medulla dividing it into triangular shapes
Renal papilla - apex of renal pyramid (duct of bellini)
What is the minor calyces?
Each renal papilla is associated with a minor calyx - where urine collects
What is the major calyx?
Minor calyces merge to form a major calyx
What is the renal pelvis?
Urine passes through major calyx to the renal pelvis
Flattened and funnel shaped structure
What is the renal hilum?
Deep fissure that marks the medial margin of each kidney
Gateway: by which renal vessels and ureter enter and exit
What is the functional unit of the kidney?
Nephron (1.5 million in each kidney)
What is each nephron broadly made up of microscopically?
Glomerulus PCT Loop of Henle DCT Collecting duct
What is the glomerulus?
Highly specialised filter
Water, electrolytes and small molecules secreted from blood
Only plasma cells and proteins remain in the blood
Afferent arterioles and efferent arterioles
20% of blood filtered at one time, 80% is removed via efferent arterioles almost immediately
What is the PCT?
Proximal convoluted tubule Major site of reabsorption 60/70% Na+ and H2O 80/90% K+ ~90% bicarbonate 100% aa's and glucose Water follows osmotic gradients
Reabsorbed materials leave by peritubular arterioles
What is the loop of henle?
Further site of reabsorption which is more regulated than in the PCT
Creates a gradient of increasing osmolarity in the medulla by countercurrent multiplication
Allows formation of concentrated urine if water has to be conserved
Thin descending limb, thin ascending limb, thick ascending limb
What is the DCT?
Distal convoluted tubule
Major site of variable reabsorption of electrolytes and water
Fluid leaving loop of henle is hypotonic
Removes more Na+ and Cl-
Actively secretes H+ ions (acid base balance)
Water may or may not follow reabsorption of electrolytes
If it doesn’t a large volume of dilute urine is formed - diuresis
What is the collecting duct?
Passed through high osmolarity environment of medulla (created by LoH)
If water can cross the epithelium it will lead the urine down the osmotic gradient - produce low volume of concentrate urine
If it cannot- urine remains dilute
What hormone systems are involved in sodium and water recovery?
Na+ recovery- renin angiotensin system, control ECF volume
Water recovery- ADH dependent, control permeability of DCT and collecting duct to water; controls ECF osmolarity
Describe the renal blood supply
Renal artery - segmental - interlobar- arcuate - interlobular - afferent arterioles - glomerulus - efferent arterioles - - - renal vein
Kidneys receive about 20% of cardiac output
Renal artery arises from abdominal aorta at level of L1/L2 immediately below superior mesenteric artery
Due to position of aorta and IVC the right renal artery is longer than the left
What are supernumerary renal arteries?
2 or more arteries to a single kidney
Most common vascular anomaly
25-40%
Describe the course of the ureters
The ureters arise from the renal pelvis on the medial aspect of each kidney at transverse processes , before descending towards the bladder on the front of the psoas major muscle (moving laterally to medially). The ureters cross the pelvis brim near the bifurcation of the iliac arteries (cross anteriorly over the common iliac), under the uterine artery/ductus deferens and down the pelvic sidewall to insert in the posterior surface of the bladder in an oblique manner
What is the relevance of the ureter piercing the bladder in an oblique manner?
Creates a one way valve where high intramural pressure collapses the ureters preventing back flow of urine
Compare and contrast ureters in a female and a male
Females
- Ureters close to ovaries as they cross the pelvic brim
- Be careful not to damage ureters in an ovariectomy esp. in ligation of ovarian arteries
- 2cm superior to ischial spine- ureters run underneath the uterine artery: in a hysterectomy where the uterus and uterine artery are removed ureter is in danger of being accidentally damaged - water under the bridge
Males
- in men, instead of uterine arteries the vas deferens cross the ureters anteriorly
What bony landmarks are used for the course of ureters?
Bony Landmarks for Course of Ureters
- Arise at ~level of L2
- Descend in front of tips of Lumbar spine transverse processes
- Cross into pelvic brim roughly in front of the sacroiliac joint
- Enter the bladder (Vesico-ureteric junction) at the level of the Ischial spines
Important for x rays too- as ureters are soft tissue and so are difficult to see
What is the arterial supply (and venous drainage) of the ureters?
Abdominal: Renal artery and testicular/ ovarian artery
Pelvic: Superior and inferior vesicle arteries
What is the nervous supply to the ureters?
Renal, testicular/ ovarian and hypo gastric plexuses
Sensory fibres from ureter enter spinal cord at T11-L2
Ureteric pain in dermatomal areas
Where are kidney stones most likely to form blockages?
1) the junction of the renal pelvis and ureter
2) point at which the ureters cross the pelvic brim
(Iliac bifurcation)
3) where the ureters pass into the wall of the urinary bladder
Describe the location of the bladder
Sits right behind the pubic bone in an adult (above it in a child)
Distended upwards when it fills with urine
What is the function of the bladder?
Collection, temporary storage and expulsion of urine (bladder muscle contraction and sphincter relaxation)
Where is the bladder embryologically derived from?
Hind gut
What is the shape of the bladder when empty and when filling?
Empty - flattened by overlying intestines
Filling - oval shaped
What is the structure of the bladder?
Hollow organ, distensible, folded, internal rugae
Apex- located superiorly, pointing towards pubic symphysis, connected to umbilicus by medial umbilical ligament (remnant of Urachus)
Body- main part of bladder between apex and fundus
Fundus/ Base- located posteriorly, triangular, apex facing backwards
Neck- formed by convergence of fundus and 2 inferolateral surfaces, joins bladder and urethra
What is the trigone of the bladder?
2 entrances of the ureters and the 1 exit of the urethra in the bladder
Triangular area within the fundus -smooth walls unlike rest of the bladder
What sphincters do females have?
External spinchters
What spinchters do males have?
Internal (prevent ejaculate entering the bladder- circular smooth muscle fibres under autonomic control) and external spinchters (skeletal muscle, voluntary, relaxes in urination to allow urine flow)
What muscle is found in the bladder?
Smooth muscle- detrusor muscle
Fibres orientated in 3 directions - maintains structural integrity when stretched
SNS & PNS innervation
Contracts during micturition (urination)
What is the arterial supply of the bladder?
Internal iliac vessels - superior vesicle branch
Obturator and inferior gluteal arteries (small branches)
Males- + inferior vesical artery too
Females- + vaginal arteries too
What is the venous drainage of the bladder?
Vesical venous plexus- internal iliac vein(hypogastric vein)
What is the nervous supply of the bladder?
Autonomic and somatic
- SNS–> hypo gastric nerve (T12-L2)
- somatic –> pudendal nerve (S2-S4)
Sensory afferent nerves found in bladder wall- need to urinate with a full bladder
Relaxing of detrusor muscle promotes urine retention, and external spinchter constricts/ relaxes
What is the bladder stretch reflex?
Primitive spinal reflex- urination stimulated in response to stretch
Toilet training in infants - spinal reflex overridden by higher centres of brain- gives voluntary control over micturition
Reflex arc
- Bladder fills with urine and bladder walls stretch, sensory nerves detect stretch and transmit information to spinal cord
- Interneurons in spinal cord relay signal to PS efferents (pelvic nerve)
- Pelvic nerve acts to contract the detrusor muscle and stimulate micturition
Non functional post childhood but needs to be considered in spinal injuries and neurodegenerative diseases
What is the urethra?
Vessel that transports urine from the bladder to external opening in perineum
Describe the male urethra
15-20cm long
Exit for semen and urine
Pre-prostatic - internal urethral orifice, neck of bladder, passes through wall of bladder, ends at prostate
Prostatic- passes through prostate gland, ejaculatory and prostatic ducts drain into urethra here
Membranous- passes through pelvic floor and deep perineal pouch; surrounded by external urethral spinchter - volume control of urination
Spongy- passes through bulb and corpus spongiosum of pelvis, ends at external urethral orifice, glans penis, urethra dilates- navicular fossa, bulbourethral glands empty into proximal urethra
Describe the female urethra
Short ~ 4cm
Predisposes women to UTIs
Begins at neck of bladder passes inferiorly through perineal membrane and muscular pelvic floor
Opens directly into perineum in an area between labia minora (vestibule)
Within the vestibule the urethral orifice is located anteriorly to the vaginal opening and 2-3 cm posterior to clitoris -distal end of urethral marked by 2 mucous glands on either side
What mesoderm is the embryonic kidney derived from?
The embryonic kidney and gonad both originate from the urogenital ridge, a region of intermediate mesoderm.
Describe pronephros
The first kidney system, never functions in humans. However, it produces the pronephric duct, which extends from the cervical region to the cloaca and drives the development of the next stage (becoming the Mesonephric duct)
Describe mesonephros
The mesonephros sprouts tubules that develop caudal to the pronephric region. These tubules plus the Mesonephric duct makes up the embryonic kidney.
The Mesonephric duct also sprouts the ureteric bud, which induces development of the definitive kidney. The Mesonephric duct also has an important role in the development of the reproductive system in the male.
Describe metanephros
The Ureteric bud sprouts from the Mesonephric duct. It induces the development of the definitive kidney within the intermediate mesoderm of the caudal region of the embryo that lies closet to it.
The ureteric bud then expands and branches into this differentiated intermediate mesoderm, the metanephric blastema, forming the definitive kidney’s structure.
The ureteric bud drives the development of the definitive kidney. The collective system is derived from the ureteric bud itself.
The excretory component is derived from the intermediate mesoderm under the influence of the ureteric bud.
How do the kidneys ‘ascend’?
The metanephric kidney first appears in the pelvic region. It then undergoes an apparent caudal to cranial shift, crossing the arterial fork formed by vessels returning blood from the foetus to the placenta.
However the kidneys don’t actually move. Development is cranial to caudal, and the trunk just extends downwards, making it appear as though the kidneys
What is renal agenesis?
The ureteric bud fails to interact with the intermediate mesoderm. Can affect one (unilateral) or both (bilateral) kidneys.
Dgescribe renal migration defects
If a kidney fails to cross the arterial fork (as the kidneys don’t actually move its more the fork snags the kidney as it develops, pulling it down), it ends up much lower than it should be (A).
During their ‘ascent’ the kidneys lie extremely close to one another. If they both get caught on the arterial fork they can fuse and form a horseshoe kidney (B).
Describe duplication defects of the kidney
Splitting of the ureteric bud, either partial or complete can lead to abnormalities. The systemic consequence is an ectopic opening, for example into the vagina or urethra, bypassing the bladder and causing incontinence.
Describe cystic kidney disease
Multicystic Kidney Disease – Atresia of ureter
Polycystic Kidney Disease – Recessive, presents early, poor prognosis.
Describe abnormal renal vessels
As the kidneys ascend they require new arterial supply, and the previous supply disappears. If it remains, they are accessory, or supernumerary arteries. These arterials are end arteries, as the main renal artery will not branch to supply that area of the kidney if an accessory artery is present. This means there is no collateral supply.
Describe the formation of the urinary bladder
The bladder is a hindgut derivate, meaning it is derived from the caudal portion of the primitive gut tube formed during embryonic folding in the fourth week of development. The caudal portion is a dilated, blind pouch called the cloaca. The cloaca is separated from the outside by the cloacal membrane, one of the two mesoderm-less regions left present after gastrulation.
The cloaca is divided by the urorectal septum into the urogenital sinus (future bladder and urethra) and anorectal canal (future rectum and anal canal).
Also involved in the development of the bladder is the allantois, which is a superoventral diverticulum of the hindgut and extends into the umbilical cord. The lumen on the allantois becomes obliterated to become the urachus, which is the median umbilical ligament in adults.
Describe some features of the male bladder
o Mesonephric ducts (MD) reach the urogenital sinus (UGS)
• Drains Embryonic urine into the cloaca
o Ureteric Bud (UB) Sprouts from MD
• Ureteric bud will become ureter opening into the bladder
o Smooth musculature begins to appear
• Will become the trigone of the bladder
o UGS begins to expand
o UBs and MDs make independent openings in UGS
Describe the female bladder
The female bladder develops in much the same way, but without male hormones the Mesonephric duct regresses. Therefore females do not form prostates or the tubes of the male reproductive system.
Describe the formation of the urethra
The female urethra is formed by the pelvic part of the urogenital sinus.
The male urethra is divided into four parts: o Pre-Prostatic o Prostatic o Membranous o Spongy
The first three parts are analogous to the female urethra. The spongy urethra is the phallic part.
Describe exstrophy of the bladder/ urachal anomalies
A congenital anomaly in which part of the urinary bladder is present outside the body. It occurs due to maldevelopment of the lower abdominal wall, leading to a rupture that causes the bladder to communicate with the amniotic fluid.
Exstrophy of the bladder may be due to a urachal fistula. This is a patent urachus, which normally becomes the median umbilical ligament. If it remains as a duct, it will connect the bladder to the umbilicus.
Describe hypospadias
A defect in fusion of urethral folds. The urethra opens onto the ventral surface, rather than at the end of the glans. The incidence of this is increasing.
What is the functional histology of the renal corpuscle (glomerulus and bowmans capsule)?
Parietal layer- simple squamous epithelium
Filtration barrier layer- fenestrations capillary endothelium
Visceral layer- podocytes- invest in endothelium making filtration slits
-produces ultra filtrate of plasma
What is the functional histology of the proximal convoluted tubule?
Simple cuboidal epithelia with pronounced brush border
-reabsoprtion begins
What is the functional histology of the loop of henle?
Thin descending and thin ascending limb- simple squamous epithelium no brush border (like a small capillary without RBCs)
- no active transport- reabsorption
Thick ascending limb- simple cuboidal epithelium, no brush border, circular lumen
- active transport- reabsorption
What is the functional histology of the distal convoluted tubule?
Simple cuboidal epithelium with lots of mitochondria and no brush border (larger lumen than pct)
Juxtaglomerular cells and extra glomerular mesangial cells- macula densa of DCT
- reabsorption- active transport
What is the functional histology of the collecting duct?
Simple cuboidal epithelium, no brush border, (larger lumen and more irregular than thick ascending limb of loop of henle)
- no reabsorption
- transport
What is the functional histology of the ureter?
Transitional epithelia, 2 smooth muscle layers (3 in lower 1/3)
- transport of urine from kidney to bladder
What is the functional histology of the bladder?
Transitional epithelia, 3 smooth muscle layers, outer Adventitia
-storage of urine
Describe glomerular filtration
The millions of afferent arterioles each deliver blood to a single nephron, and the diameter of each afferent arteriole is slightly greater than the diameter of the associated efferent arteriole. This diameter difference increases the pressure of the blood inside the glomerulus. This increased hydrostatic pressure helps to force the below components out of the blood in the glomerular capillaries. However, only 20% of the delivered blood is actually filtered, 80% exits via the efferent arteriole.
o Most of the water
o Most/All of the salts
o Most/All of the glucose
o Most/All of the urea
The above are all filtered, as they are relatively small particles. RBCs and plasma proteins are not filtered, as they are too large. The size limit for filtration is molecular weight 5,200 or an effective molecular radius of 1.48nm. Further to this the basement membrane and podocytes glycocalyx have negatively charged glycoproteins, which repel protein movement.
The water and solutes that have been forced out of the glomerular capillaries pass into Bowman’s space and are called the glomerular filtrate or the ultrafiltrate.
Describe the 3 layers of the filtration barrier
There are three layers to pass through:
1. Capillary endothelium
o Water, salts, glucose
o Filtrate moves between cells
2. Basement Membrane
o Acellular gelatinous layer of collagen/glycoproteins
o Permeable to small proteins
o Glycoproteins (-‘ve charge) repel protein movement
3. Podocyte Layer
o Pseudopodia interdigitate to form filtration slits
What three physical forces are required in glomerular filtration?
Plasma filtration is only due to three physical forces.
- Hydrostatic pressure in the capillary (can be regulated) (PGC)
- Hydrostatic pressure in Bowman’s capsule (PBC)
- Osmotic pressure difference between the capillary and tubular lumen (pGC)
Why is charge important in filtration? What happens if the negative charge on the filtration barrier is lost?
Neutral Molecule – The bigger it is, the less likely to get through
Anions – Negative charge also repels, more difficult to get through
Cations – Positive charge allows slightly bigger molecules through
In many disease processes, the negative charge on the filtration barrier is lost so that proteins are more readily filtered. This condition is called proteinuria (protein in the urine).
What is the normal charge of the filtration barrier?
Negative
Describe tubular reabsorption
Only about 1% of glomerular filtrate actually leaves the body, the rest is reabsorbed into the blood as it passes through the renal tubules. This process is called tubular reabsorption and occurs via three mechanisms, osmosis, diffusion and active transport.
It is called reabsorption and not absorption as these substances have already been absorbed once (particularly in the intestines).
Reabsorption in the PCT is isosmotic, and driven by sodium uptake. Other ions accompany sodium to maintain electro-neutrality, e.g. Chloride and Bicarbonate.
Solutes move from Tubular lumen to Intersticium to Capillaries, and reabsorption can either be transcellular or paracellular (around cells through tight junctions).
Describe tubular reabsorption of sodium
- Na+ is pumped out of tubular cells across the basolateral membrane by 3Na-2K-ATPase.
- Na+ moves across the apical (luminal) membrane down its concentration gradient
o This movement of Na+ utilises a membrane transported or channel on the apical membrane. - Water moves down the osmotic gradient created by the reabsorption of Na+
Describe tubular reabsorption of glucose
Glucose is reabsorbed in the PCT using the Na-Glucose Symporter SGLUT. This moves glucose against its concentration gradient into the tubule cells. Glucose then moves out of the tubule cell on the basolateral side by facilitated diffusion.
100% of glucose is normally reabsorbed, but the system has a maximum capacity, or Transport Maximum (Tm). If the plasma concentration exceeds Tm, the rest spills over into the urine. If this happens, water follows into the urine, causing frequent urination (polyuria).
Describe secretion
Secretion provides a second route, other than glomerular filtration, for solutes to enter the tubular fluid. This is useful as only 20% of plasma is filtered each time the blood passes through the kidney. It also helps to maintain blood pH (7.38 – 7.42). The substances secreted into the tubular fluid are: o Protons (H+) o Potassium (K+) o Ammonium ions (NH4+) o Creatinine o Urea o Some hormones o Some drugs (e.g. penicillin)
How are organic cations secreted in the PCT?
- Entry by passive carrier
a. Mediated diffusion across the basolateral membrane down favourable concentration and electrical gradients, created by the 3Na-2K-ATPase pump. - Secretion into the lumen
a. H+-OC+ exchanger that is driven by the H+ gradient created by the Na+-H+ Antiporter.
How is co transport and active transport involved in tubular reabsorption and secretion?
Different segments of the tubule have different types of Na+ transporters and channels in the apical membrane. This allows Na+ to be the driving force for reabsorption, using the concentration gradient set up by 3Na-2K-ATPase (active transport). o Proximal Tubule • Na-H Antiporter • Na-Glucose Symporter (SGLUT) o Loop of Henle • Na-K 2Cl Symporter o Early Distal Tubule • Na-Cl Symporter o Late Distal Tubule and Collecting Duct • ENaC (Epithelial Na-Cl)
What is clearance and how is it calculated?
The volume of plasma from which a substance (X) can be completely cleared to the urine per unit time
The renal artery is the input to the kidney and the kidney has two possible outputs, the renal vein and the ureter. Therefore, if a substance is not metabolised or synthesised, an equal amount must leave in the urine and the renal venous blood.
Clearance can be calculated with the equation:
Clearance = (amount in urine x urine flow rate) / arterial plasma conc
E.g. Substance X is present in the urine at a concentration of 100mg/ml. The urine flow rate is 1ml/min. The excretion rate of substance X is therefore: Excretion rate = 100mg/ml x 1ml/min = 100mg/min
If Substance X was present in the plasma at a concentration of 1mg/ml then its clearance would be:
Clearance = 100/1= 100ml per min
100ml of plasma would be completely cleared of substance X per minute.
Describe glomerular filtration rate
The volume of plasma from which any substance (X) is completely removed by the kidney in a given amount of time (usually 1 minute)
GFR is a measure of the kidney’s ability to filter a substance, thus overall function. It is an indication of how well the kidney works and is therefore useful in clinical practise, as a fall in GFR generally means kidney disease is progressing and vice versa.
To measure GFR, a substance (X) must be freely filtered across the glomerulus. This substance must not be reabsorbed, secreted or metabolised by the cells of the nephron. It must pass directly into the urine. Examples of substances that can be used to calculate GFR are Creatinine and Inulin.
GFR= (amount in urine x urine flow rate) / arterial plasma concentration
Normal GFR for Males = 115 – 125 ml/min
Normal GFR for Women = 90 – 100 ml/min
What is renal plasma flow?
The kidney receives ~1.1 litres of blood a minute. About 45% of this is RBCs and 55% is plasma.
We can therefore calculate renal plasma flow. 55% of 1.1L = 605ml/min of plasma.
What is filtration fraction?
Filtration fraction is the proportion of a substance that is actually filtered.
If renal plasma flow is 605ml/min, and 20% of all plasma is filtered, 125ml/min is filtered through into Bowman’s space (normal GFR), and 480ml passes through into peritubular capillaries.
Filtration fraction = glomerular filtration rate / renal plasma flow
Filtration Fraction is about 20%. (125/605 = 20.8)
How is renal blood flow and GFR regulated?
Autoregulation:
Auto-regulatory mechanisms keep the GFR within normal limits when arterial BP is within physiological limit (80-80 mmHg).
Myogenic Response:
Arterial BP rises –> Afferent Arteriole Constriction
Arterial BP falls –> Afferent Arteriole Dilation
Tubular Glomerular Feedback (TGF):
Changes in tubular flow rate as a result of changes in GFR change the amount of NaCl that reaches the distal tubule. Macula densa cells respond to these changes.
If NaCl increases:
- Response is GFR needs to decrease
- Adenosine released, causes vasoconstriction of afferent arteriole
If NaCl decreases:
- Response is GFR needs to increase
- Prostaglandins released causing vasodilation of afferent arteriole
What are the two types of aminoaciduria?
General overflow aminoaciduria
Specific overflow aminoaciduria
What is General overflow aminoaciduria?
All AA’s present in the urine. This is normally due to inadequate deamination in the liver, or an increased GFR. It is often seen in early pregnancy.
What is Specific overflow aminoaciduria?
Only a specific AA is present in the urine. This is usually due to a genetic inability to break down one AA, e.g. phenylalanine in PKU (lack of phenylalanine hydroxylase).
How can aminoaciduria lead to stone formation?
Renal aminoaciduria is mainly confined to the dibasic acids, and it due to a genetically determined lack of the specific transport protein(s). For some reason cysteine is an abnormally insoluble amino acid, especially in acidic urine, and cystinuria may be associated with stone formation.
What regulates volume of blood?
Na+ balance - (and thus any water that follows)
What regulates osmolarity of plasma?
Water balance
Where is the water in the body generally located?
2 simple compartments- ECF and ICF separated by a cell membrane
What salt is the main determinant of ECF volume?
ECF volume (which includes the vascular system) is determined largely by the concentration of NaCl in the ECF
How does the concentration of NaCl affect the effective circulating volume?
If sodium in ECF changes then volume if ECF changes and affects the ECV and thus affects blood pressure too
Why don’t we just add/remove water to plasma to change the ECF plasma volume? (As opposed to changing the concentration of NaCl)
As this would change plasma osmolarity
So instead we move osmoles (NaCl) and water follows
If NaCl excretion < intake how does this affect plasma volume?
Increases plasma volume - greater reabsorption of NaCl in kidney - more water drawn out of nephron - increases blood pressure
If NaCl excretion > intake how does this affect plasma volume?
Decreases plasma volume - less reabsorption of NaCl in kidney - less water drawn out of nephron - decreases blood pressure
How much sodium of that in the filtered load is reabsorbed in the PCT?
67%
How much sodium of that in the filtered load is reabsorbed in the descending limb of the LoH?
0%
How much sodium of that in the filtered load is reabsorbed in the ascending limb of the LoH?
25%
How much sodium of that in the filtered load is reabsorbed in the DCT?
~5%
How much sodium of that in the filtered load is reabsorbed in the collecting duct system?
3%
How much water of that in the filtered load is reabsorbed in the PCT?
65%
How much water of that in the filtered load is reabsorbed in the descending limb of LoH?
10-15%
How much water of that in the filtered load is reabsorbed in the Ascending limb of LoH?
0%
How much water of that in the filtered load is reabsorbed in the DCT?
0%
How much water of that in the filtered load is reabsorbed in the Collecting duct system?
5% (during water loading)
>24% (during dehydration)
What is the relevance of the 67% sodium that is reabsorbed in the PCT?
67% is always absorbed regardless of actual amount that is filtered/ GFR
Autoregulation prevents GFR from changing too much but if any changes occur despite this, glomerular tubular balance blunts the Na+ excretion response
What is glomerular tubular balance?
Balance between GFR and rate of absorption of solutes
Must be kept as constant as possible, so if GFR increases, rate of reabsorption must also increase
What pump is sodium reabsorption driven by? And where is this located?
3Na+-2K+-ATPase on basolateral membrane
What types of sodium transporters does section 1 of the PCT have on its apical membrane?
Section 1 - Na+ reabsorption
Cotransporter with glucose
Na-H exchange
Cotransporter with amino acid/ carboxylic acids
Cotransporter with phosphate (increase in PTH)
Aquaporin
[urea/Cl-] creates a conc gradient for Cl- reabsorption in section 2 and 3
What types of sodium transporters does section 2 and 3 of the PCT have on its apical membrane?
Section 2 &3- Na+ and water reabsorption Na-H exchanger Paracellular Cl- reabsorption Transcellular Cl- reabsorption Aquaporin- sets up osmole gradient favouring water uptake from lumen
How is isosmotic reabsorption a hallmark for the PCT?
PCT is highly permeable to water
Allows reabsorption of Na+ to be isosmotic with water
The tight coupling between Na+ and water reabsorption is called isosmotic reabsorption. This bulk reabsorption of Na+ and water (the major constituents of ECF) is critically important for maintaining ECF volume
What are the 3 forces /gradients that drive water reabsorption in the PCT (isosmotic reabsorption)?
Osmotic gradient established by solute reabsorption
Hydrostatic force in intersticium
Osmotic force in peri tubular capillary due to loss of 20% filtrate at glomerulus, but cells and proteins remained in blood
Is sodium reabsorption in the loop of henle isosmotic?
No, water and sodium reabsorption is separated
What does the descending limb of the LoH reabsorb?
Reabsorbs water but not NaCl
What does the ascending limb of the LoH reabsorb?
Reabsorbs NaCl but not water- known as the DILUTING SEGMENT (dilutes NaCl in the filtrate and so therefore tubule fluid leaving the loop is therefore hypoosmotic (more dilute) compared to the plasma)
Describe sodium reabsorption wrt volume, in the thick and thin descending limbs of the LoH
Increase in IC [Na+] set up by PCT allows for para cellular reuptake of water from the descending limb (no tight junctions)
Concentrates Na+ and Cl- in the lumen of the descending limb ready for active transport in the ascending limb
Describe sodium reabsorption wrt volume, in the thick and thin ascending limbs of the LoH
Impermeable to water
Na+ reabsorption is passive- water reabsorption in descending limb creates a gradient for passive Na+ ion reabsorption in thin ascending limb
Epithelia have loose junctions - permits para cellular reabsorption of Na+
NaCl transported from lumen into cells by NaKCC2 channel (apical)
Na+ then moves into intersticium due to action of 3Na-2K+-ATPase (basolateral)
K+ ions diffuse back into lumen via ROMK
Cl- ions move into intersticium
What channel in the ascending limb of the LoH acts as a target for loop diuretics?
NaKCC2 is target for loop diuretics - increased loss of K + in urine - hypokalaemia
Describe sodium reabsorption wrt volume, in the DCT
Water permeability of early DCT is fairly low and active reabsorption of Na+ results in dilution of filtrate
Hypoosmotic (more dilute) fluid enters from the loop and 5-8% Na+ is actively transported by NaCC2 transporter driven by 3Na+-2K+-ATPase
Major site of Ca2+ reabsorption via PTH
Further dilution means that fluid leaving is more hypoosmotic
What channel in the DCT acts as a target for thiazide diuretics?
NaCC2 transporter
Describe sodium reabsorption wrt volume, in the collecting duct
Region responsible for fine tuning filtrate
Able to respond to a variety of stimulants and has 2 distinct cell types
Principal cells (70%) - reabsorb Na+ by Epithelial Na+ Cell (ENaC) driven by 3Na+-2K+-ATPase
- Produces lumen charge - electrical gradient for para cellular Cl- reabsorption and K+ secretion into lumen
- Variable water uptake through Aquaporin 2 - dependent on ADH
- Have a more distinct membrane than intercalated cells
Intercalated cells
- Active reabsorption of chloride
- secrete H+ ions or HCO3-
Which region of the nephron is most sensitive to hypoxia and why?
Thick ascending limb of LoH
This region uses more energy than any other region of the nephron, and is particularly sensitive to hypoxia
Needs energy for active transport
What is the short term control of blood pressure?
Baroreceptors (aortic arch and carotid body)
What are the four broad long term regulators of blood pressure?
RAAS
ADH
ANP
SYMPATHETIC NERVOUS SYSTEM
Describe RAAS wrt blood pressure
Reduced perfusion pressure in the kidney detected by baroreceptors in the afferent arteriole, causes the release of renin from the granular cells of the juxtaglomerular apparatus.
Decreased NaCl Concentration at the Macula Densa cells (Due to low perfusion and therefore low GFR) causes Sympathetic stimulation to the JGA. This also increases the release of renin.
(Also causes Macula Densa cells to release Prostaglandins –> Afferent Vasodilation)
Renin cleaves Angiotensinogen à Angiotensin I, which is in turn cleaved by Angiotensin Converting Enzyme (ACE) to form the active hormone Angiotensin II.
Angiotensin II
There are two types of Angiotensin II receptors, AT1 and AT2. They are both G-protein coupled receptors. Angiotensin II’s main actions are via the AT1 receptor
Actions of Angiotensin II
o Vasoconstriction
• Works on vascular smooth muscle cells, increases TPR thus BP
• Vasoconstriction of afferent and efferent arteriole
o Aldosterone
• Stimulates the adrenal cortex to synthesise and release Aldosterone
• Aldosterone stimulates Na+ and therefore water reabsorption
• Acts on principal cells of CD
• Activates ENaC and apical K+ channels
• Increases basolateral Na+ extrusion via 3Na-2K-ATPase
o Sympathetic Activity
o Increase Na+ reabsorption
• Stimulates Na-H exchanger in the apical membrane of PCT
o Thirst
• Stimulates ADH release at hypothalamus
o Breaks down Bradykinin
• Bradykinin is a vasodilator
What are the actions of angiotensin II?
o Vasoconstriction
• Works on vascular smooth muscle cells, increases TPR thus BP
• Vasoconstriction of afferent and efferent arteriole
o Aldosterone
• Stimulates the adrenal cortex to synthesise and release Aldosterone
• Aldosterone stimulates Na+ and therefore water reabsorption
• Acts on principal cells of CD
• Activates ENaC and apical K+ channels
• Increases basolateral Na+ extrusion via 3Na-2K-ATPase
o Sympathetic Activity
o Increase Na+ reabsorption
• Stimulates Na-H exchanger in the apical membrane of PCT
o Thirst
• Stimulates ADH release at hypothalamus
o Breaks down Bradykinin
• Bradykinin is a vasodilator
Describe the SNS wrt blood pressure
• Vasoconstriction by α1-adrenoceptors
• Inc. force/rate of heart contraction β1-adrenoceptors
o Decreased Renal Blood flow
• Decreased GFR and Na+ excretion
• Activates Na/H exchanger in PCT
o Stimulates renin release from juxtaglomerular cells
• Increased Angiotensin II/Aldosterone levels
Describe ADH wrt blood pressure
The baroreceptor reflex works well to control acute changed in BP. It produces a rapid response, but does not control sustained increases as the threshold for baroreceptor firing resets.
A 5-10% drop in blood pressure causes low-pressure baroreceptors in the atria and pulmonary vasculature to send signals to the brainstem via the vagus nerve. This activity modulates both sympathetic nerve outflow, secretion of the hormone ADH and reduction of ANP release.
A 5-150% change in blood pressure causes high-pressure baroreceptors (carotid sinus/aortic arch) to send impulses via the vagus and glossopharyngeal nerves. A decrease in blood pressure will increase sympathetic nerve activity and the secretion of ADH.
Actions of ADH
o Addition of Aquaporin to Collecting Duct
• Reabsorption of water
• Forms concentrated urine
• Release stimulated by increases in plasma osmolarity or severe hypovolemia
o Thick Ascending Limb
• Stimulates apical Na/K/Cl co-transporter
• Less Na+ moves out into the medulla, reduced osmotic gradient for water to exit the lumen into the peritubular capillaries from the thin descending limb
What are the actions of ADH?
o Addition of Aquaporin to Collecting Duct
• Reabsorption of water
• Forms concentrated urine
• Release stimulated by increases in plasma osmolarity or severe hypovolemia
o Thick Ascending Limb
• Stimulates apical Na/K/Cl co-transporter
• Less Na+ moves out into the medulla, reduced osmotic gradient for water to exit the lumen into the peritubular capillaries from the thin descending limb
Describe ANP wrt blood pressure
Acts in the opposite direction to the others
o Synthesised and stored in atrial myocytes
o Promotes Na+ excretion
• Vasodilation of afferent arteriole
o High BP à Stretch Atrial Cells
• Increased release
• Increased Na+ excretion, volume decreases, BP decreases
o Low BP à Atrial Cells less stretched
• Reduced release
• Reduced Na+ excretion, volume increases, BP increases
o Inhibits Na+ reabsorption along the nephron
What is hypertension?
Sustained increase in blood pressure
What is mild hypertension?
> 140/90 on more than 3 occasions
What is moderate hypertension?
> 160/100
What is severe hypertension?
> 180/110
What is essential hypertension?
In around 95% of cases, the cause is unknown. This is known as Essential Hypertension. Genetic and environmental factors may both be involved and the pathogenesis is unclear.
What is secondary hypertension?
Where a cause can be defined, hypertension is referred to as secondary hypertension. Here it is important to treat the primary cause. Examples include: o Renovascular disease o Chronic Renal Disease o Aldosteronism o Cushing’s syndrome
How does conns syndrome cause hypertension?
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How does Cushing’s syndrome cause hypertension?
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How does renal vascular disease cause hypertension?
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How does phaeachromocytoma cause hypertension?
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How can hypertension be treated (4 medications)?
o ACE Inhibitors
• Prevent the production of Angiotensin II from Angiotensin I
• Angiotensin II receptor antagonists
o Thiazide Diuretics
• Inhibit NaCC co-transporter on apical membrane of DCT
• May cause hypokalaemia (more K+ lost in urine)
o Vasodilators
• Ca2+ channel blockers, reduce Ca2+ entry into smooth muscle cells
• α1 receptor blockers, reduce sympathetic tone
o Beta Blockers
• Block β1-receptors in the heart
• Reduces heart rate and contractility
Non-pharmacological approaches to the treatment of hypertension include diet, exercise, reduced Na+ intake, reduced alcohol intake.
How is plasma osmolarity regulated?
By water balance
What receptors directly sense changes in plasma osmolarity?
Hypothalamic osmoreceptors
Where are hypothalamic osmoreceptors found?
Located in hypothalamus in organum vasculoum of laminae terminal is (OVLT) anterior and ventral to 3rd ventricle
What 2 pathways do the hypothalamic osmoreceptors stimulate once stimulated themselves?
ADH and thirst pathways
Which pathway senses SMALL changes in plasma osmolarity?
ADH
Which pathway senses large changes in plasma osmolarity (>10%) ?
Thirst
Where is ADH produced, stored and secreted from?
Made in hypothalamus
Stored and secreted from posterior pituitary
Describe how ADH works?
ADH acts in kidney and affects renal water excretions
ADH controls water loss
Slight increase in osmolarity- effect on ADH?
Increase in osmolarity
Increase in ADH
Decrease in urine
Increase in water reabsorption
Slight decrease in osmolarity- effect on ADH?
Decrease in osmolarity
Decrease in ADH
Increase in urine
Decrease in water reabsorption
How does ADH affect the glomerulus?
Vasoconstriction
How does ADH affect the ascending LoH?
Increases Na+, K+, Cl- reabsorption
How does ADH affect the DCT?
Increase water reabsorption
Aquaporin 2 insertion
Apical membrane does not contain water channels in the absence of ADH- held below the surface and can be rapidly inserted when required
ADH binds to receptor–> PKA signalling –> AQP2 inserted into apical membrane
How does ADH affect the cortical CD?
Increases water reabsorption (AQP2)
Increases K+ reabsorption
How does ADH affect the medullary CD?
Increase water reabsorption (AQP2)
Urea reabsorption acts as an effective osmole
What is the relevance of urea recycling in the medullary part do the collecting duct?
ADH also increases the permeability of the medullary part of the collecting duct to urea, causing its reabsorption. This in turn causes water to follow. The rise in urea concentration in the tissues causes it to passively move down its concentration gradient into the ascending limb, which is permeable to Urea but impermeable to H2O. Urea then passes back into the collecting duct, where it is reabsorbed in the medullary portion and more water follows. Urea is therefore recycled.
What is SIADH?
SIADH – Syndrome of Inappropriate Anti-Diuretic Hormone secretion
In SIADH the secretion of ADH is not inhibited by the lowering of blood osmolarity (negative feedback is removed).
This means that excessive amounts of water is retained, causing blood osmolarity to drop and cause hyponatremia (Low blood Na+ concentration). Symptoms of hyponatremia include nausea and vomiting, headache, confusion, lethargy, fatigue, appetite loss, restlessness and irritability, muscle weakness, spasms, cramps, seizures and decreased consciousness or coma.
If hypernatremia comes about because of SIADH the condition may be treated with ADH Receptor Antagonists.
Explain the relationship between volume and osmolarity balance?
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What is diabetes insipidus?
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Describe the corticopapillary osmotic gradient
At the cortico-medullary border, there is no osmotic gradient. However the medullary Intersticium is hyperosmotic up to 100 mOsmol/Kg at the papilla. There is a gradient of increasing osmolarity as you descend.
The active transport of NaCl out of the TAL and the recycling of urea sets up the osmotic gradient. The action of the TAL is crucial, removing solute without water, diluting the filtrate and increasing Intersticium osmolarity.
If you block the NaK2Cl transporters in the TAL with a loop diuretic (E.g. Furosemide) the medullary Intersticium becomes isosmotic and large amounts of dilute urine is produced.
Describe countercurrent multiplication
The Loop of Henle acts as a counter current multiplier, to set up the osmotic gradient:
Tubule filled initially with isotonic fluid.
Na+ ions are pumped out of the ascending loop (Na/K/2Cl co-transporter), raising the osmotic pressure outside the tubule and lowering it inside.
(Max concentration difference inside to out is 200 mOsmol/L).
Fresh fluid enters from the glomerulus, and enters the descending limb. As the descending limb is permeable to water, it leaves via osmosis to raise the osmotic pressure inside the descending tubule to 400mOsmol/L.
More fluid enters from the glomerulus, pushing the concentrated (400mOsmol/L) fluid into the ascending limb.
The Na+ pump then produces another 200 mOsmol/L gradient across the membrane.
But it started with a more concentrated solution (400mOsmol/L).
So external osmolarity rises to 500mOsmol/L.
Fresh fluid again enters; water leaves via osmosis until the osmotic pressure in the descending tubule is 500mOsmol/L.
This is then pushed into the ascending limb, where the Na+ pump produces yet another 200 mOsmol/L gradient, raising the interstitial osmolarity to 700mOsmol/L.
The final gradient will be limited by the diffusional process.
Describe countercurrent exchange
The concentration gradient that the loop of Henle sets up would not last long though without the Vasa Recta.
These are blood vessels that run alongside the loops, but with opposite flow direction. This counter-current flow allows for the maintenance of the concentration gradient.
Isosmotic blood in the descending limb of the vasa recta enters the hyperosmotic milieu of the medulla, where there is a high concentration of ions (Na+, Cl-, Urea). These ions therefore diffuse into the vasa recta and water diffuses out.
The osmolarity of the blood in the vasa recta increases as it reaches the tip of the hairpin loop, where it is isosmotic with the medullary Intersticium.
Blood ascending towards the cortex will have a higher solute content than the surrounding Intersticium, so solutes move back out. Water will also move back in from the descending limb of the loop of Henle.
Therefore, although there is a large amount of fluid and solute exchange across the vasa recta, there is little net dilution of the concentration of the interstitial fluid because of the U shape of the vasa recta allowing it to act as a counter current exchanger.
The vasa recta therefore do not create the medullary hyperosmolarity, but do prevent it from being dissipated.
Why is it important to maintain concentration of calcium within set limits?
Calcium plays a critical role in many cellular processes: o Hormone secretion o Nerve conduction o Inactivation/activation of enzymes o Muscle contraction o Exocytosis
What are the set limits that calcium is usually maintained within?
the body very carefully regulates the plasma concentration of free ionised calcium ([Ca2+]), the physiologically active form of the metal, and maintains free plasma [Ca2+] within a narrow range (1.0 - 1.3mmol/L).
What is the composition of calcium in plasma?
In plasma, calcium exists as:
o Free ionised species – 45% (Active Form)
o Protein Bound – 45%(80% to Albumin)
o Complexed– 10% (Citrates, phosphate etc)
How do the intestines control Ca2+?
The absorption of Calcium is under the control of Vitamin D. About 20-40% of dietary calcium (25mmol) is absorbed and some is excreted back into the gut (2-5mmol).
Absorption increases in growing children, pregnancy, lactation and decreases with advanced age. Complexing calcium (e.g. with oxalates) reduces its absorption
How do the kidneys control Ca2+?
The kidneys filter 250mmol of Calcium per day, 95-98% of which is reabsorbed, giving a urinary calcium excretion of < 10mmol/day. o 65% Reabsorbed in PCT • Associated with Na+ and water uptake o 20-25% Reabsorbed in loop of Henle o 10% Reabsorbed in DCT • Under the control of PTH
How are vitamin D and PTH involved in control of Ca2+?
Parathyroid Hormone (PTH) regulates the conversion of Calciferol in the kidney to its active form, Calcitriol. Calcitriol is the active form of Vitamin D and works by binding to Calcium in the gut to increase its absorption.
- Vitamin D2 Absorbed by Gut Nil
- (Prohormone) Vitamin D3 Skin (UV light)Nil
- (Prohormone) Calciferol Liver (1st Hydroxylation of Vit D) Nil
- (Prohormone) Calcitriol Kidney (2nd Hydroxylation of Vit D), Ca2+ absorption (Binds to Ca2+ in the Gut)
- Parathyroid Hormone Parathyroid Gland Conversion of Calciferol to Calcitriol Ca2+ release from bone Ca2+ reabsorption in kidney
PTH also affects calcium levels directly; by increasing it’s release from bone and its reabsorption in the PCT of the kidney. It also decreases the reabsorption of phosphate and bicarbonate, as if they are present in the blood with Calcium stones will form.
Calcium levels regulate PTH via negative feedback.
What are some causes of hypercalcaemia?
o Primary hyperparathyroidism
• ~ 1/1,000 of the general population
o Haematological malignancies
o Non-Haematological malignancies
Hypercalcaemia of malignancy comes about due to the production of Parathyroidhormone-Related Peptide (PTHrP). This peptide has AA homology with the active portion of PTH and works to increase plasma Ca2+ concentration via the mechanisms shown above.
What are some symptoms of hypercalcaemia?
o Gastrointestinal • Anorexia • Nausea/Vomiting • Constipation • Acute pancreatitis (rarely) o Cardiovascular • Hypertension • Shortened QT interval on ECG • Enhanced sensitivity to digoxin • Renal • Polyuria and polydipsia • Occasional nephrocalcinosis o Central Nervous System • Cognitive difficulties and apathy • Depression • Drowsiness, coma
How is hypercalcaemia managed?
o General measures
• Hydration – Increase Ca2+ excretion
• Loop diuretics – Increase Ca2+ excretion
o Specific Measures
• Bisphosphonates – Inhibit the breakdown of bone
• Calcitonin – Opposes the action of PTH
o Treat underlying condition
Describe renal stones
Approximately 20% of men and 5-10% of women will develop renal stones in their lifetime, and 70-80% of all renal tract stones are made of Calcium. Factors involved in their formation include low urine volume, hypercalcuria and low urine pH (< 5.47). The mechanism of stone formation is complex, and involves the super-saturation of urine with calcium oxalate.
Conservative management of renal stones includes increasing fluid intake, restricting dietary oxalate and sodium, and considering the dietary restriction of calcium and animal protein.
Acid base balance
Potassium concentration
A
How much sodium of that in the filtered load is reabsorbed in the PCT?
67%
How much sodium of that in the filtered load is reabsorbed in the descending limb of the LoH?
0%
How much sodium of that in the filtered load is reabsorbed in the ascending limb of the LoH?
25%
How much sodium of that in the filtered load is reabsorbed in the DCT?
~5%
How much sodium of that in the filtered load is reabsorbed in the collecting duct system?
3%
How much water of that in the filtered load is reabsorbed in the PCT?
65%
How much water of that in the filtered load is reabsorbed in the descending limb of LoH?
10-15%
How much water of that in the filtered load is reabsorbed in the Ascending limb of LoH?
0%
How much water of that in the filtered load is reabsorbed in the DCT?
0%
How much water of that in the filtered load is reabsorbed in the Collecting duct system?
5% (during water loading)
>24% (during dehydration)
What is the relevance of the 67% sodium that is reabsorbed in the PCT?
67% is always absorbed regardless of actual amount that is filtered/ GFR
Autoregulation prevents GFR from changing too much but if any changes occur despite this, glomerular tubular balance blunts the Na+ excretion response
What is glomerular tubular balance?
Balance between GFR and rate of absorption of solutes
Must be kept as constant as possible, so if GFR increases, rate of reabsorption must also increase
