Systems 2 - Renal Flashcards
Water % in body
60% of body weight is water (40-45L)
1/3 of this is extracellular fluid
2/3 of this is intracellular fluid
Extracellular fluid includes interstitial fluid, plasma, transcellular fluid
It has ~150mmol/L cations - mainly Na⁺
~150mmol/L anions - mainly Cl⁻
–> doesn’t add up to 300mmol, Na⁺ and Cl⁻ do not completely dissociate
Functions of the kidneys (6)
To maintain water balance To maintain salt balance Contribute to pH regulation Excretion of nitrogenous waste products Conservation and regulation of essential substances Hormone secretion
Functions of the kidneys - maintaining water balance
Extracellular fluid has osmolarity of ~285mOsm/L
Number of particles present determine osmolarity, mainly comprised of salts, v small amount protein
Regulated by water intake (thirst) and output
Functions of the kidneys - maintaining salt balance
Extracellular concentrations of:
[Na⁺] 135-145 mMol/L
[Cl⁻] 96-106 mMol/L
(can only fluctuate a very small amount)
Functions of the kidneys - pH regulation
Extracellular pH ~ 7.4 (very narrow limit)
–> urine is slightly acidic, to rid body of acid
pH is regulated by the rate at which H⁺ and HCO₃⁻ are excreted in urine
[HCO₃⁻] 25mMol/L - regulated by lungs via the rate at which CO₂ is expired
Functions of the kidneys - excretion of nitrogenous waste products
Urea, ammonia, creatine, uric acid
Excreted only by kidney
Functions of the kidneys - conservation and regulation of essential substances
Glucose Amino acids Magnesium [Phosphate] 1.1 mMol/L [K⁺] 3.6-5.2 mMol/L [Ca²⁺} 1.2 mMol/L - especially important for cardiac function
Functions of the kidneys - hormone secretion
Active form vitamin D - for absorption of calcium and phosphate from the gut (so bone problems if renal failure)
Renin - via RAAS for control of bp
Erythropoietin - for synthesis of RBCs (anaemia if renal failure)
Various prostaglandins
Osmolarity vs osmolality
Osmolarity = mOsmoles/L in solution
Osmolality = mOsmoles/kg in solvent
Normally equal, as density of water is one
Kidney response to dehydration and overhydration
Dehydration
- output of 0.3ml/min at osmolarity of 1,200 mOsm/L
- antidiuresis
Overhydration
- output of 12-15ml/min at osmolarity of 85 mOsm/L
- diuresis
But both have blood osmolarity of 285 mOsm/L - can excrete urine 4x more or less concentrated than extracellular fluid
- not rapid operator, takes time
Gross anatomy of the kidney
Cortex - darker, granular - Bowman’s capsules
Medulla - lighter, parallel striations pointing out - loops of Henle and collecting ducts
Features of the nephron - proximal convoluted tubule
Cuboidal epithelial cells
Many mitochondria - lots of active transport
Brush border of microvilli on apical cell surface
Tight junctions to regulate amount of fluid transport
Two sections - pars convolute and pars recta - pars convolute has most microvilli and mitochondria
-> paracellular and transcellular fluid reabsorption
Isosmotic reabsorption, osmolarity of tubular fluid remains ~300mOsm/L
MOST SALT AND WATER REABSORPTION OCCURS HERE (60-70%)
Features of the nephron - descending limb of Loop of Henle
Thin
Squamous epithelia
No brush border
Few mitochondria
Features of the nephron - ascending limb of Loop of Henle
Thick
Cuboidal epithelia
No brush border
Many mitochondria
Features of the nephron - distal convoluted tubule
No brush border - less fluid transport than in PCT
Many mitochondria
Features of the nephron - collecting duct
Columnar epithelia
No brush border
Many mitochondria
-> still some reabsorption occuring
Juxtaglomerular apparatus
Where nephron (top of ascending limb of LOH) bends back and closely contacts the glomerular capillaries in Bowman’s capsule
Modified smooth muscle cells line the afferent arteriole - juxtaglomerular cells - packed with secretory granules instead of actin and myosin, secrete renin
Macula densa - modified DCT cells - sensitive to Na⁺ concentration, will stimulate juxtaglomerular cells to release renin when Na⁺ low
Mesangial cells cushion - contractile tissues to support fragile tissues around
Movements across nephron
Reabsorption from tube to capillary - Na⁺, Cl⁻, K⁺, HCO₃⁻, glucose, amino acids
Secretion from capillary to tube - H⁺, K⁺
- dense capillary network needed
- glomerular filtration rate 90-120ml/min
Capillary network around nephron
Glomerular capillary bed
Peritubular capillary bed - in cortex, around PCT and DCT
Vasa recta - starts in cortex, but mainly in medulla - mirrors loop of Henle
Subcapsular nephrons vs juxta-medullary nephrons
SUBCAPSULAR NEPHRONS
- glomeruli in outer renal cortex
- short proximal tubules
- short loops of Henle, just dipping into medulla
- short, poorly developed vasa recta
JUXTA-MEDULLARY NEPHRONS
- glomeruli deep in cortex, close to corticomedullary boundary
- long proximal tubules
- long loops of Henle extending to renal pelvis before doubling back
- long vasa recta extending to renal pelvis
- -> better at absorbing glomerular filtrate
Glomerular filtration
Rate of 90-120ml/min
- urine output is 1ml/min, so kidneys reabsorb 99% of filtrate (necessary as filtration is unselective)
Varies with age (falls as age), gender (lower in women), body surface area (higher increases). 50% increase in early pregnancy
Energy is from hydrostatic pressure of blood, as heart beats
No energy expenditure by kidney in filtration
Contents of glomerular filtrate
No cells
Trace amounts of protein
Ions and small organic substances (glucose, amino acids) in the same concentration as they are present in plasma - ultrafiltrate
-> Glomerulus is filtration barrier, has ‘functional’ pores of 8-10nm diameter
Rate of glomerular filtration depends on:
1) Molecular weight - less than 10kDa is freely filtered, 10-80kDa rate is proportional to weight, more than 80kDa is totally excluded
2) Shape - long thin molecules more easily filtered than spherical molecules of same MW
3) Electrical charge - easiest to filter +ve charge, then neutral, hard to filter -ve
Three barriers to a substance passing from blood
1) Through fenestrations in wall of glomerular capillary
- 100nm diameter, so too large to prevent protein passage
2) Glomerular basal lamina
- glycoprotein matric, non-cellular
- carries fixed negative charge
- gives electrical characteristics of pores
3) Inner epithelial lining - podocytes
- have processes extending out, so substance has to pass through slit pores to enter Bowman’s capsule
- gives mechanical characteristics
-> damage to podocytes or basement membrane -> protein loss in urine
Glomerular filtration rate equation
= K x S x [(Pɢᴄ - Pᴛ) - (πɢᴄ - πᴛ)]
= permeability of glomerular barrier x surface area available for absorption x [(net hydrostatic pressure favouring filtration) - (net colloid osmotic pressure opposing filtration)]
ɢᴄ = in glomerular capillaries ᴛ = in Bowman's capsule
πᴛ = 0 usually, as should be no proteins in Bowman’s capsule
Afferent vs efferent ends of glomerular capillaries
AFFERENT - way in
- most filtration here, as higher driving pressure for filtration
EFFERENT - way out
- virtually no filtration here (but never -ve so reabsorption)
- blood here has high colloid osmotic pressure, many proteins, and high haematocrit (conc RBCs), not much fluid -> so viscous, slower blood flow
Pathologies affecting GFR
Kidney stones/tumour (blockage) - prevent the free drainage of fluid, increases hydrostatic pressure in tubule, so decrease rate
Nephrotic syndrome - increased permeability (K), so increase rate - also decreases colloid osmotic pressure in glomerular capillaries, so increase rate
Kidney removed - decrease SA, so decrease rate
Low bp - lowers hydrostatic pressure in glomerular capillaries, so decrease rate
Bloc
Autoregulation
= the relative independence from systemic bp of GFR and renal blood flow over the physiological range of MABP (80-180mmHg)
- GFR and renal blood flow remain ~constant when the kidneys are isolated and denervated, so must be a protective mechanism to separate from MABP
Brain most protected, then heart, then kidney
In vivo varies more
How to measure/estimate GFR
Inulin clearance - very accurate, inconvenient as exogenous
Creatinine clearance - accurate, quite convenient
Serum creatinine level - variable accuracy (depends where falls on graph), very convenient
[Blood urea] - not accurate
Radioisotope elimination - expensive, and dangerous exposure
Needs to be a substance freely filtered at glomerulus, but undergoing no tubular transport
Filtration rate = excretion in urine rate
Rate of filtration equations
Rate of filtration of X = Px x GFR
(Px = plasma conc of X)
Rate of excretion of X = Ux x V
(Ux = urinary conc of X V = rate of urine output)
As rate excretion = rate filtration
-> Px x GFR = Ux x V
GFR = (Ux x V)/Px
Creatinine clearance as measure of GFR
Best to use
Endogenous, produced at constant rate so stable plasma concentration
Doesn’t completely follow laws - some creatinine secreted to PCT, so urine creatinine comes partly from secretion, not all filtration
But degree of error is the same, increase Ux and increase Px (top and bottom of equation)
So works as a measure - non invasive, can do yourself at home - 24hr urine collection, blood sample
ENDOGENOUS
EASY
STABLE
Serum creatinine concentration to measure GFR
Serum creatinine can be converted to an estimate of GFr, when corrected for body size, gender, ethnicity
Good - the individual should stay relatively constant
Curve is no. functional nephrons/GFR on bottom, serum creatinine at side
Only useful at end point of curve, where less than one functional kidney, as beginning is flat
Used to plot progression of renal disease, as serum creatinine increases
PAH to measure renal blood flow
= para aminohippuric acid
Exogenous
Removed almost entirely from renal blood in a single circulation - freely filtered, secreted in active transport into tubular fluid in PCT, where it hijacks the secretory process for endogenous uric acid
Clearance very high, approximately same rate that plasma is delivered to kidneys
Renal blood flow equation
Renal blood flow = renal plasma flow/1-haematocrit
= 700/1-0.45
= 1.27L/min - out of 5L/min cardiac output, 25% to kidneys!
Vitamin D synthesis
Cholesterol (from food)
↓ sunlight
Cholecalciferol
↓ liver
25 hydroxycholecalciferol -> if no PTH, excreted inactive
↓ kidney, with parathyroid hormone
1,25 dihydroxycholecalciferol = active vitamin D
Vitamin D function, and consequences of deficiency
Increases absorption of calcium and phosphate from gut
Increases reabsorption of calcium and phosphate by kidney
-> important for bone metabolism and maintaining Ca²⁺ in normal range
-> also for cardiovascular and immune function
Deficiency - rickets (deformed bones in children)
- osteomalacia (weak bones in adults)
Synthesis of erythropoietin
Decreased O₂ delivery to renal cortex - from CO poisoning, anaemia, haemmorhage, stenosis, altitude, respiratory disease
↓
O₂ sensors in renal cortex near basal membrane
↓
Hypoxia inducible factor
↓
Increased rate of transcription of EPO gene by renal cortical interstitial cells
↓
Erythropoietin
↓
Erythrocytes - bone marrow cells produce
Recombinant human EPO
Used in renal failure, cancer, AIDs
And by athletes to boost RBCs - can tell difference between endogenous and exogenous in urine samples
Pronephric phase of kidney development
3rd-4th week
Hollow tube high up in embryo
Never filters blood or has any use
Nephric duct built, with capacity to drain urine
Mesonephric phase of kidney development
4th-8th week
Transient role
Individual nephrons assemble at top, then die away with last function at bottom of embryo
(can retain trace of this, 2 kidneys bilaterally each with ureter)
Metanephric phase of kidney development
5th week onwards
Becomes definitive adult kidney
Sprouts from nephric duct become pelvis and ureter
Tail of nephrogenic mesoderm will be cortex
Nephric (uteric) duct will grow collecting tubules and nephrons into mesoderm from 6 weeks -> past birth following trigger from mesoderm
-> so epithelia that make up nephron are mesenchymal
Kidneys grow upwards (and what can go wrong)
Start in pelvis, pushed up by uteric bud as it grows up
Stop when reach adrenal glands
- if pushed too high -> thoracic kidney
- if not high enough, can’t overcome lump of common iliac vessels -> pelvic kidney
- if low and trapped by inferior mesenteric artery, fuse together -> horseshoe kidney
Polycystic kidney
Common, debilitating
Needs to be removed as is useless
Fatal if bilateral - can be corrected in utero if caught early
Where channels pump the wrong way, or an obstruction stops correct flow -> inflates kidney
Circulation of amniotic fluid
Amniotic fluid largely made of urine
Foetus practises swallowing and breathing with it, cycles many times
-> problem if blind ended, as urine is toxic
Separation of urogenital sinus and rectum
Week 5 - undivided cloaca
Week 6 - enroaching of urorectal septum
Week 8 - separate urogenital and anal orifices (still unclear if male or female though, genital tubercle only)
Some urine drains into allantois, to umbilicus, must be sealed before birth
If not, patent urachus
Incomplete cloaca separation
Blind ended rectum, can be high or low (easier to repair if low)
Or fistula, rectum into urogenital sinus or vagina
Ureter formation
Initially is outgrowth of mesonephric duct
Then obtains separate entrance to bladder
Forms trigone, two ureters and urethra
Mesonephric ducts travel down to join to urethra instead - can now be used in males to add sperm without passing bladder, and females will kill
Types of kidney disease
Prerenal - loss of bp/effective blood volume
Intrarenal - inflammation, drugs/toxins
Postrenal - bladder or prostate cancer, stone
or systemic - lupus nephritis, myeloma kidney, vasculitis, HIV, drug toxicity
Oedema - in kidney disease?
Isolated oedema
or
Oedema in nephrotic syndrome - low serum albumin, proteinuria
Measuring kidney function
Creatinine - 90 normal
eGFR - more than 90 normal, less than 10 -> severe impairment
U and Es - urea and electrolytes
Ultrasound (USS)
Dipstick test - should have no protein, blood, free haemoglobin or glucose, and pH of 4.5-8.5
Renal replacement therapy types and associated complications
Haemodialysis - access complications, acute complications (arrhythmias, CVS death, air embolism), long term complications (left ventricular hypertrophy)
Peritoneal dialysis - many complications, associated with increased intra-abdominal pressure
Transplant - need to fit enough, need donor, immunosuppression. Early complications (delayed function, rejection, surgery), late complications (malignancy, infections), and other complications (CVS disease, disease reoccurence)
Functions of components of nephron
Glomerulus - ultrafiltration (tubular fluid = plasma without proteins)
PCT - mainly reabsorption
Loop of Henle - concentrates tubular fluid to ensure not excessive water loss
DCT - final tuning before pass to ureters
Urine = (filtrate - reabsorbed substances) + secreted substances
Tubular reabsorption
Blood leaving efferent arteriole and entering peritubular capillaries/vasa recta has characteristics favouring reabsorption of salts and water:
- low hydrostatic pressure
- high colloid osmotic pressure (rich in plasma proteins)
- high haematocrit, so sluggish blood flow
Renal clearance
Clearance = (Ux x V)/Px
Ux = urine conc of X V = urine flow rate Px = plasma conc of X
= rate at which substance is cleared from blood plasma.
Reflects the extent that a substance is filtered at the glomerulus and its subsequent movements (reabsorption or secretion) across the walls of the nephron.
Clearance rate and GFR - if no tubular transport
Filtration rate + tubular transport = Excretion rate
Tx = tubular transport = 0
(Px x GFR) + 0 = Ux x V
SO
GFR = (Ux x V)/Px
GFR = clearance rate (100ml/min)
eg inulin, creatinine
Clearance rate and GFR - if net reabsorption
Tx is positive
Px x GFR < Ux x V Filtration rate < excretion rate
GFR > (Ux x V)/Px GFR > clearance rate
eg glucose (100% reabsorbed), amino acids, Na⁺
Clearance rate and GFR - if net secretion
Tx is negative
Filtration rate > excretion rate
GFR < clearance rate
eg PAH, H⁺
Use of knowing clearance rate vs GFR
Take clearance value and compare to GFR If clearance bigger, net secretion If clearance smaller, net reabsorption If equal, no tubular transport So can know how the kidney handles a substance
Passive transport
Downhill movemetn, no metabolic energy expended directly
Down electrical, osmotic or concentration gradient
Active transport
Uphill movement, expending metabolic energy
Primary - eg Na/K ATPase
Secondary - eg Na/amino acid cotransporter
- indirect use of energy, couples movement of one substance against a concentration gradient with movement of another substance with its concentration gradient (driving ion)
Transport maximum limited processes
All active transport systems have a transport maximum, Tm
Tm = limit for amount of substance that can be transported per unit time
- transport process saturated when all binding sites on carrier protein are occupied, eg diabetes mellitus->glucose in urine
Plasma conc of Tm is the renal threshold
Tm limited transport of glucose
Above 11 mMol/L, glucose is excreted (some splay, not every nephron has same number of transporters)
Usually increase plasma glucose, increase reabsorption, until saturation
Not tight regulation
Tm limited transport of phosphate
Above 1.4mMol/L, filtered and excreted
Very tightly regulated by kidney, removed from body even if only slightly above normal range
Tubular transport of sodium in proximal tubule
Na⁺/H⁺ countertransporter into epithelial cell (from lumen)
Na⁺/K⁺ ATPase out to blood
Tubular transport of glucose and amino acids in proximal tubule
Na⁺/glucose or amino acid cotransporter into epithelial cell (from lumen) - secondary active transport
Facilitated diffusion out to blood
- all must be reabsorbed, can’t lose amino acids or glucose in urine
Tubular transport of water, K⁺,Cl⁻, Ca²⁺ and urea in proximal tubule
Paracellular and transcellular movement of water from lumen to blood. Paracellular water moves via osmotic gradient, transcellular movement not influenced by body conditions
K⁺,Cl⁻, Ca²⁺ and urea follow concentration gradients paracellularly, and some transcellularly
Tubular transport of proteins in proximal tubule
In via endocytosis
Amino acids cleaved
Out by facilitated diffusion
Tubular transport of organic acids and bases in proximal tubule
Organic bases - out into tubular fluid via carriers, exchange for Na⁺ or H⁺
Organic acids - out into tubular fluid via carriers, exchange for Cl⁻ or HCO₃⁻
These are key secretions into urine, some endogenous and some exogenous
Handling of drugs in proximal tubule
Secreted by Tm limited transport to lumen of tubule:
ACIDS
- uric acid (endogenous)
- PAH, aspirin, penicillin (exogenous) - will compete for removal from the body, coadministration -> longer lasting effect
BASES
- creatinine, histamine (endogenous)
- morphine (exogenous)
Rate of secretion depends on pH of tubular fluid, when tubular fluid is acidic more base is secreted, and vice versa
Can test urine to see how well drug will be excreted
Tubular transport of hydrogen and bicarbonate in proximal tubule
Na⁺/H⁺ countertransporter pumps H⁺ into tubular fluid
Reabsorbs HCO₃⁻, which combines with H⁺ to form CO₂ and H₂O in presence of carbonic anhydrase, then goes to blood
- because no HCO₃⁻ transporters in apical membrane, need to break down and reform
- HCO₃⁻ is essential to buffer pH in the body, needs to be reabsorbed. H⁺ is just recycled
Concentrations entering loop of Henle vs leaving vs urine
Tubular fluid entering loop = conc of plasma, 300mOsm/L
Leaving loop is more dilute, 100 mOsm/L
BUT urine excreted is more concentrated, 1200mOsm/L
-> collecting duct concentrates fluid, due to conditions set up by LOH
Loop of Henle as a countercurrent multiplier
Osmotic gradient in the renal medulla, which collecting ducts pass through. Only 200mOsm/L difference transversely , small amount of energy across establishes large gradient
Longer LOH, larger osmotic gradient, more concentrated urine
Descending limb freely permeable to salt and water
- so lots of water loss to salty environment, some salt moves in
- > very concentrated fluid at bottom of loop
Ascending limb is impermeable to water
- so no water reabsorption, but salt moves out via many transporters
- > very dilute fluid going to DCT (but in smaller volume of water)
Vasa recta as countercurrent exchange
All NaCl in and water out will return in ascending limb, so same concentration on exiting as on entering the vasa recta - maintains blood concentrations
If there was route out for blood at bottom of loop, it would be at osmolarity of 1200mOsm/L, taking salt also and leaving very concentrated blood
Functions of vasa recta
- Provide nutrients and oxygen to renal medulla
- Remove CO₂ and other metabolic waste products generated by cells in renal medulla
- Reabsorb 20% glomerular filtrate from fluid in loop of Henle
- Reabsorb a variable amount of salt and water from collecting ducts
Urea in the nephron
50% of urea filtered is reabsorbed into blood from proximal tubule
50% is recycled and added again to descending limb down its concentration gradient -> allowed to leave as urine when need to retain water
ADH adds urea transporters (as well as aquaporins) in medullary collecting ducts
Distal nephron
= distal convoluted tubule + collecting duct (cortical and medullary)
Recieves less than 20% of glomerular filtrate
No brush border
Many mitochondria
- For fine adjustments in volume and composition of urine
- Excress H⁺ excreted here, important role in acid-base balance
K⁺ regulation in nephron
Essential, as is principal determinant of membrane potential
80% reabsorbed before distal tubule - via Na⁺K⁺2Cl⁻ cotransport and paracellularly
K⁺ secretion by principal cells
K⁺ reabsorption by intercalated cells
K⁺ secretion and reabsorption
PRINCIPAL CELLS
K⁺ secretion - dominates in healthy western diet
From extracellular fluid into distal nephron cell via exchange for Na⁺
Then secretion into tubule lumen
INTERCALATED CELLS
K⁺ reabsorption
Into cells from lumen via exchange for H⁺
Into extracellular fluid
Aldosterone effects on nephron
Increase K⁺ secretion
Increase Na⁺, H₂O, Cl⁻ reabsorption
Increase H⁺ excretion
Continues as long as concentration gradient
Need fresh flow of blood, increased flow for increased excretion
- why need K⁺ sparing diuretics, can wash out lots of K⁺
H⁺ and HCO₃⁻ movement in nephron
Intercalated cells
For acid-base balance
Makes new HCO₃⁻ to replenish any lost
In PCT, H⁺ is recycled and reabsorbed, can’t lose any
In DCT, can excrete appropriate amount of H⁺
H⁺ is from excess metabolism, and from CO₂ + H₂O
Once H⁺ exits cell, NH₃⁻ and HPO₄²⁻ mop up, act as urinary buffers
Collecting duct
Runs parallel to ascending limb of loop of Henle, with flow in opposite direction
Cortical and medullary both impermeable to water and urea with no ADH present
ADH only makes medullary section permeable to urea, makes both sections permeable to water
In normal ADH -> 1.4L urine/day at 300-800mOsmol/L
(more ADH -> more urine, lower osmolarity)
Water treatment by location
65% reabsorbed in PCT
20% reabsorbed in loop of Henle
14% reabsorbed in DCT and collecting tubule
1% lost to urine
Nephrotic syndrome features
Proteinuria
Hypoalbuminaemia (low protein in blood)
-> Hyperlipidaemia
Oedema
Classification of nephrotic syndrome
Familial/inherited
Acquired/primary - unclear why, largest group
- includes minimal change nephrotic syndrome (MCNS), focal segmental glomerulosclerosis
Secondary (to systemic disease)
Clinical complications of nephrotic syndrome
THROMBOSIS
- Haemoconcentration (high conc of RBCs), -> slow peripheral circulation
- Increase in prothrombotic clotting factors (fibrinogen, VII, X, VIII)
- Decrease in anti-thrombin and plasminogen
INFECTIONS
- Immunological losses (less Igs), and drugs eg steroids from nephrotic syndrome
HYPOTHYROIDISM
- Loss of thyroid binding globulin
HYPERLIPIDAEMIA
Nephrotic syndrome treatment options
Steroids - 90% with MCNS initially respond, 40% frequently relapse
Cytotoxics - cyclophosphamide, cyclosporin A or Tacrolimus
Monoclonal anti-CD20 antibody - rituximab
Steroid Resistant Nephrotic Syndrome (SRNS)
Older age group
May be primary or secondary - all patients will have gene panel tested, 30% with causative gene mutation, 70% have immune based disorder
Segmental sclerosis, foot process effacement
50% will get renal failure within 5 years.
Of those with transplant, 50% get early disease reccurence after transplant, so circulating factors influence
Congenital nephrotic syndrome
Rare, inherited
Proteinuria in utero or early infancy
-> rapid onset end stage renal failure
No response to steroids or other agents, transplant only option (when old enough)
Due to breakdown in glomerular filtration barrier at podocyte level
General management of nephrotic syndrome
Symptomatic control of fluid shift
Immunosuppression
- low sodium diet, fluid restriction, diuretics
- treat infections promptly
Osmosis definition
Movement of water from a region of low solute concentration to one of high solute concentration across a semipermeable membrane
- semipermeable is permeable to water, not solute
Osmolality definition
Concentration of solutes per kg of solvent - the number of particles exerting a drawing effect on water
Isosmolar definition
If the concentration of solutes is equal in extracellular and intracellular fluid
Isotonic definition
If cell is placed in a solution and there is no net water movement across the cell membrane
Body regulates by keeping extracellular concentrations as stable as possible, by kidney
Hypotonic
Water enters cells
Cell swells, may burst
Extracellular osmolarity lower
Hypertonic
Water leaves cells
Cells shrink
Extracellular osmolarity higher
Normal plasma osmolarity
290mOsmol/kgH₂O
- variation by just 3mOsmol is sufficient to activate compensatory mechanisms (osmoreceptors in hypothalamus detect change, indicates to posterior pituitary to release ADH
ADH
Antidiuretic Hormone = Vasopressin
Produced in posterior pituitary
- > increases water permeability of collecting duct by inserting aquaporins
- > increases urea permeability (so increases concentration gradient) in the inner medullary region of the collecting duct
- > increases NaCl reabsorption in thick ascending limb
- so aids reabsorption by the kidney (more concentrated urine), urine that is hypertonic to blood
Control of ADH release
Produced in supraoptic and paraventricular nuclei neurones
Transported to axon terminals in posterior pituitary
Released into blood by a rise of plasma osmolality of 1%, to activate hypothalmic neurones
Less release when osmolality falls
10-15 minute half life, removed by liver and kidneys - so can adjust quickly
ADH in collecting duct
ADH in blood binds to receptor on basolateral surface of tubule cell
Stimulates adenylyl cyclase to generate cAMP and activate protein kinases
Increases insertion of aquaporins into apical surface of cell, increasing water permeability
Volume urine leaving distal tubule = volume leaving as urine
Diabetes insipidus
Lack of action of ADH, so less water reabsorption from collecting duct
-> polyuria of dilute urine
-> excessive thirst
Due to
- lack of ADH production = central diabetes insipidus. Managed by desmopressin, artificial ADH. From idiopathic, or secondarily (head injuries, cancer, surgery)
- kidney not responding to ADH = nephrogenic diabetes insipidus. Inherited forms affect expression of ADH receptor or aquaporin proteins. Acquired forms from renal cysts or infections, release of uteric obstruction, release of uteric obstruction. NOT TREATABLE CLINICALLY
Syndrome of Inappropriate ADH secretion
SIADH
Increase ADH, increase water retention
-> hyponatraemia
-> elevated urine osmolality (less than 100 mOsm/L)
-> decreased serum osmolality in otherwise eurovolaemic patient
Difficult to diagnose, other factors may stimulate ADH release, eg hypotension, stress, pain, nausea
SIADH caused by nervous system disorders, pulmonary disease, neoplasia, drug-induced
Hyponatraemia
Mild - serum [Na] 130-135 mmol/L
Moderate - serum [Na] 125-129 mmol/L
Severe - serum [Na] <125 mmol/L
-> neurological defects from cell swelling
-> nausea, malaise, lethargy, decreased consciousness, headache, seizures, coma
TREAT SLOWLY, infuse with saline
Control of effective circulating volume
ECV = blood volume
Control plasma volume to regulate blood pressure
Kidneys central to control, as regulate Na⁺ - sense water volume and change Na⁺
Decreased blood volume = hypovolaemia
- > decreased cardiac filling (preload)
- > decreased stroke work, decreased cardiac output, decreased arterial bp
Increased blood volume = hypervolaemia
- > increased cardiac filling
- > increased stroke work, increased cardiac output, increased arterial bp
Hypovolaemic shock
Stage 1 - 15% volume lost, normal bp, normal urine output
Stage 2 - 15-30% volume lost
Stage 3 - 30-40% volume lost
Stage 4 - more than 40% volume lost, decreased bp, raised HR, raised resp rate, absent cap refill, pale, sweating, lethargy, coma, anuria
Low ECV ->
Lowered bp Sensed by kidney Decreased Na⁺ excretion Water retention ECV restored
High pressure sensors of ECV
Mainly systemic arterial
- arterial baroreceptors - carotid sinus/aortic arch. Sends sympathetic nerve signal -> constriction of afferent and efferent arterioles to lower GFR, and stimulates renin secretion to lose Na⁺ and lose water
- juxtaglomerular apparatus - including macula densa. Site of synthesis, storage and release of renin
RAAS
Renin Angiotensin Aldosterone System
Angiotensinogen from liver
Combines with renin from kidney
To form Angiotensin I
In lung, forms Angiotensin II in the presence of ACE (angiotensin converting enzyme)
Angiotensin II effects
Result of activated RAAS
- aldosterone release from cortex
- systemic vasoconstriction
- ADH secretion
- –> water reabsorption, increased bp
Aldosterone description
Steroid hormone
Secreted from zona glomerulosa (cortex) of adrenal glands
After stimulation by angiotensin II
- Na⁺ conserving hormone, increases Na⁺ reabsorption by nephron
- also facilitates K⁺ secretion into tubular fluid at DCT, so K⁺ loss
Slow acting
Aldosterone binding steps and results
Binds to baso-lateral receptor
Stimulates transcription of apical Na⁺ channels
Increased NaCl reabsorption via principal cells in distal tubule/collecting duct
Cl⁻ and H₂O follow Na⁺ into blood out of lumen
- also facilitates K⁺ secretion into tubular fluid at DCT, so K⁺ lost
Low pressure sensors of ECV
Cardiac atria
Pulmonary vasculature
ANP
Atrial natriuretic peptide
-> natriuresis, excretion of Na⁺ (so loss of water)
Synthesised and stored in atrial myocytes
In increased ECV, increased atrial stretch, ANP released
- > inhibition of aldosterone secretion
- > vasodilation of afferent arteriole, increase GFR
- > decreased Na⁺ reabsorption in collecting tubule
- > inhibition of renin secretion
- > inhibition of renin release
—> Increased water loss
Bacteriuria
= bacteria present in urine
‘Significant’ is arbitrary cut off, different in different scenarios
Can be asymptomatic bacteriuria
UTI = significant bacteriuria with signs and symptoms
Urethral syndrome = signs and symptoms, with NO significant bacteriuria
Predisposing factors for UTI in all groups
Instrumentation/surgery Catheterisation Obstruction Neurogenic bladder Transplantation Diabetes
Predisposing factors for UTI in adults - females and males
ADULT FEMALES Sex Lack of urination after intercourse Some contraceptives Pregnancy
ADULT MALES –> increased risk of prostatitis
Insertive rectal intercourse
Predisposing factors for UTI in the elderly - females and males
ELDERLY FEMALES
Dementia
Bladder prolapse
Oestrogen deficiency
ELDERLY MALES
Dementia
BPH (enlarged prostate)
Clinical spectrum of progression of UTIs
Urethritis - least severe Epididymo-orchitis Cystitis Urethral syndrome Prostatitis Pyelonephritis - most severe
Types of UTI
Lower UTI - urethra and bladder
Upper UTI - bladder and ureter
Uncomplicated - usual pathogen in a person with normal urinary anatomy Complicated - abnormal urinary tract - abnormal renal function - immuno-compromised - virulent organism
Most common pathogen in UTIs
E. coli - for all types of UTI
Type I fimbrae bind to urothelium
Infection via
- ascending route - most common - terminal urethra close to anus
- haematogenous
- lymphatic
Diagnosis of UTI
Urine microscopy - raised white cells, (epithelial cells -> contamination), RBCs
Urine culture - single species of organism -> UTI, if more than 10⁵ organisms/ml. If mixed growth -> contamination
UTI dipsticks - nitrites (bacteria produce nitrite form nitrate), leucocyte esterase, proteinuria, haematuria
Imaging - abdominal Xray, IVP - intravenous pyelogram - Xray of KUB with contrast, ultrasound, CT scan
Asymptpmatic bacteriuria
Only needs treatment (or identification) if
- pregancy - increased risk of pyelonephritis, low birth weight
- children younger than 5
Antibiotic therapy to UTIs
1st line - trimethoprim, nitrofurantoin, cephalexin - need to be excreted in urine, so antibiotic gets to urinary tract
Complications of lower UTI
Recurrence
Ascending pyelonephritis
Sepsis
Renal failure
In catheter, risk of blockage
Pyelonephritis
Ascending infection
Increased risk if diabetic, obstructing neuropathy, long-standing catheter
Typical:
- fever, chills, malaise, progressive flank pain, cystitis symptoms
Atypical:
- non-specific symptoms, headache, abdominal pain, pelvic pain, confusion, lethargy
–> often atypical in young children and elderly
WORSE CLINICAL OUTCOME
Utero-vesical junction
Ureters wave of peristalsis down from renal pelvis into utero-vesical junction
Ureters enter bladder wall at diagonal angle, then U turn
- means that as bladder fills, ureter is forced shut
- if it were straight (congenital abnormality), then reflux of urine into kidneys -> hydronephrosis (swollen kidneys) -> renal failure
Bladder structure
Dome is main storage (top of bladder)
Trigone is rigid base, spontaneously active - formed by two uteric orifices and bladder neck (urethral opening)
- outside peritoneum, so not affected by eg peritonitis
Bladder wall
BOTTOM LAYER - Urothelium, transitional epithelium - prone to cancer
Waterproof to prevent toxic urine penetrating wall
THEN - mucosa
THEN - detrusor smooth muscle
TOP LAYER - serosa, veins arteries etc here
Male urethra
15-20cm S shaped External sphincter complete Greater outlet resistance Risk of obstruction, as prostate enlarges with age
Female urethra
3-4cm Straight External sphincter horseshoe shaped Less outlet resistance Risk of incontinence, as low resistance (and muscles damaged in childbirth)
Smooth muscle in urethra
Sympathetic activation during storage - contract circular and relax longitudinal muscle, to increase resistance
NA acts on α1 and β3 receptors (can be selectively targeted)
Parasympathetic activation during micturition - contract longitudinal and relax circular muscle, to decrease resistance
M2/M3 receptors used - Ach to contract longitudinal, NO to relax smooth muscle, receptors are abundant in circular muscle
-> autonomic helps to change resistance, but not enough to control urine flow
Skeletal muscle in urethra
Horseshoe shaped, especially in females (incomplete ring)
So when contracted, tube kinks
Bladder filling and voiding coordination
Filling - detrusor relaxed, neck closed
Voiding - detrusor contracted, neck open
Nerve activity during bladder filling
Parasympathetic - from sacral segments - INACTIVE
Sympathetic - from lower thoracic and upper lumbar segments - MAINTAIN RELAXATION
Pudendal - from sacral segments - MAINTAIN CLOSURE of external sphincter
Higher centres controlling bladder storage/voiding
Ascending afferents -> PAG (peri-acqueductal gray)
- > ACG (anterior congulate gyrus), right insula, lateral pre-frontal cortex
- > medial pre-frontal cortex ->
IF NO VOID
- inhibition of PAG and PMC (pontine micturition centre)
IF VOID
- relax inhibition of PAG, PAG excited PMC, descending motor output to sacral spinal cord
-> relax urethral sphincter, contract detrusor, void
Nerve activity during bladder emptying
Parasympathetic - ACTIVE - Ach, detrusor contracts, relax urethra
Sympathetic - INACTIVE
Pudendal - LESS ACTIVE - external sphincter opens
Types of disorders of urinary tract function
Failure to store urine
- urgency
- increased frequency (polyuria and nocturia)
- incontinence
–> due to irritative conditions (UTIs), reduced compliance, stress incontinence, detrusor overactivity
MAINLY WOMEN
Failure to pass urine
- poor flow - often due to enlarged prostate
- terminal dribbling
- retention
–> due to bladder outflow obstruction, spinal cord injury.
MAINLY MEN
Urodynamics, and a normal trace
In hospital
Catheter via rectum into abdominal cavity (Pabd)
Catheter into bladder lumen (Pves)
- subtracted, to give Pdet, true detrusor pressure
– should only rise slightly on filling, as bladder is compliant
- to measure bladder pressures and flow
Normal: Pves increases on void Pabd decreases on void Pdet increases on void (flow will also peak here)
Poor compliance
Bladder filled with connective tissue, eg in diabetes, following surgery or radiotherapy
Detrusor pressure rises abnormally during filling
Pressure in ureters may also rise, damaging kidneys -> hydronephrosis
Micturition reflex evoked at lower filling volumes
-> flow trace has multiple small peaks as detrusor pressure increases
Stress incontinence
Involuntary urethral leakage with exertion/coughing/sneezing
Urethra not tight enough resistance
Due to damaged external sphincter or pelvic floor
-> flow as abdominal and bladder pressures increase (even if only small increase in Pdet)
Manage with tape inserted via incision in vagina and threaded behind urethra - artificially support bladder with sling
Detrusor overactivity
Involuntary detrusor contractions, impossible to defer
-> flow at low filling pressures, as detrusor contracts
Treatments for detrusor overactivity - 1st line
Muscarinic receptor antagonists
- non-selective eg OXYBUTYNIN, TOLTERODINE, SOLIFENACIN - decrease urge and frequency, can be intolerable side effects.
- M3 selective eg DARIFENACIN
Treatments for detrusor overactivity - 2nd line
β3 agonist
- eg BETMIGA
- good, but CVS effects so can’t be used in hypertension
Treatments for detrusor overactivity - 3rd line
BOTULINUM TOXIN
- injected into many points in bladder, to relax
- effective, but need general anaesthetic, and repeat every 8 months
Bladder outlet obstruction
Increased resistance in urethra
-> retention of urine, problem as increases pressures, can reflect to kidney
Common as prostate enlarges with aging, BPH (benign prostatic hyperplasia)
-> flow delayed after detrusor pressures rise
- hesitancy
- decreased flow rate
- incomplete bladder emptying
- stopping and starting voiding
Treatment of BPH - relax small prostate
(prostate contains smooth muscle with α1 receptors, detrusor is β)
α adrenergic receptor blockers:
- non-selective - PHENOXYBENZAMINE
- selective short acting α1 - PRAZOSIN, ALFUZOSIN, INDORAMIN
- selective long acting α1 - TERAZOSIN, DOXAZOSIN
- α1A selective - TAMSULOSIN, SILODOSIN
Treatment of BPH - shrink large prostate
(growth depends on conversion of testosterone to dihydrotestosterone (active) by enzyme 5-α-reductase)
Inhibit 5-α-reductase:
- 5α type II blocker - FINASTERIDE
- 5α type I and II blocker - DUTASTERIDE
Treatment of BPH - removal of prostate tissue
Final line treatment
- transurethral resection (cauterise) - TURP
- microwave thermotherapy - TUMT
- radiowaves - TUNA
- high energy lasers vaporise - PVP
Spinal cord injury causing flow problems
Where control by brainstem over sacral spinal cord coordination of bladder and outflow tract is lost
-> bladder contracts against high resistance, so voiding is poor
NO TREATMENT
Diuretics - uses, function, 5 classes
Used in - oedema, congestive heart failure, hypertension
To decrease reabsorption of Na⁺, so water loss
Osmotic Carbonic anhydrase inhibitors Loop Thiazides Potassium sparing
Osmotic diuretics - mechanism
MANNITOL
- pharmacologically inert, doesn’t act on receptors is just highly osmotic substance
- increases plasma osmolarity, increases osmotic pressure so decreases water reabsorption
- filtered at glomerulus and poorly reabsorbed - hence why can’t use glucose or NaCl
Osmotic diuretics - uses and side effects
MANNITOL
Used:
- forced diuresis (poison)
- acute glaucoma
- cerebral oedema
-> slow IV infusion, can’t be too fast or neurones will dehydrate
Side effects - draws fluid from brain and eyes, so dry mouth, dizziness etc
Carbonic anhydrase inhibitor diuretics - mechanism
ACETAZOLAMIDE
- suppresses CA, so less H⁺ production, less Na⁺/H⁺ exchange, less Na⁺ into cell, less water in
- increases excretion of HCO₃⁻, so alkaline urine -> metabolic acidosis
- —> BUT effect is self-limiting, body will find another way to produce H⁺ to maintain pH
Not used much, not very potent
Carbonic anhydrase inhibitor diuretics - uses and side effects
ACETAZOLAMIDE
Used:
- glaucoma
- metabolic alkalosis
- prophylaxis of altitude sickness, as alkalosis increases breathing, decreases CO₂
Side effects - dizziness, headache, blurred vision, loss of appetite, stomach upset
Loop diuretics - mechanism
FUROSEMIDE
- inhibits Na/K/2Cl cotransporter (into blood)
- so +ve ions build up in lumen, water stays in lumen
- > torrential urine production
(most common diuretic)
Loop diuretics - uses and side effects
FUROSEMIDE Used: - heart failure - pulmonary oedema - hypertension - hepatic cirrhosis with ascites - nephrotic syndrome - renal failure - hypercalcaemia Side effects: Renal function - hypovolaemia/hypotension, hypokalaemia, metabolic alkalosis Unrelated - dose-related hearing loss, allergic reactions
Thiazides - mechanism
HYDROCHLOROTHIAZIDE
- inhibits Na/Cl cotransporter
- Na⁺ builds up in tubule, so decreased water reabsorption
- – +ve charge also causes increased Ca²⁺ reabsorption
Self-limiting effect, as blood volume decreases, renin secreted to distal tubule, angiotensin formation, aldosterone secretion -> so limited effect
Thiazides - uses and side effects
HYDROCHLOROTHIAZIDE
Used:
- adjunct in congestive heart failure/hypertension
- nephrogenic diabetes insipidus
— long term diuretic, not very potent
Side effects:
Renal function - hypokalaemia, metabolic alkalosis, hypocalciuria, hypomagnesaemia, hyponatraemia
Unrelated - hyperuricaemia precipitating gout (as compete with uric acid for tubular secretion), hyperglycaemia (impaired pancreatic release of insulin), increased plasma cholesterol
K⁺ sparing diuretic - ENaC blocker
TRIAMTERENE, AMILODERONE
- directly block epithelial Na⁺ channel in distal tubule, collecting tubule, collecting ducts
- used with loop and thiazide diuretics to maintain K⁺ balance
Side effects - hyperkalaemia, GI disturbance, rashes
K⁺ sparing diuretic - Aldosterone antagonists
SPIRONOLACTONE
Early phase - increase opening of ENaC
Late phase - promotes DNA transcription to increase synthesis of ENaC and increase synthesis of Na/KATPAse
- adjunct therapy in heart failure, or in hyperaldosteronism (primary or secondary)
Side effects - hyperkalaemia, GI disturbance, menstrual disorders or testicular atrophy
Clinical uses of diuretics - cardiac decompensation
Loop diuretics
Thiazides
K sparing diuretics
- need to maintain K balance as low [K⁺] will increase toxicity of digitalis
Clinical uses of diuretics - hypertension
Thiazides
Loop diuretics
- need to maintain K balance as low [K⁺] can be fatal with ACE inhibitors, angiotensin receptor antagonists or B blockers
Clinical uses of diuretics - ascites
Loop diuretics
Thiazides
- to keep patient comfortable and conserve proteins
Clinical uses of diuretics - chronic and acute renal failure
Chronic - less effective if primary. May decrease GFR in high doses
Acute - not reccomended
AKI
Acute Kidney Injury
= function of kidneys not as good as (few weeks ago)
- diagnosed with raised creatinine (suggesting decreased GFR)
- marker for many problems in body
Causes of AKI
PRERENAL - most common
- decreased perfusion of kidney - blood loss, eg shock
RENAL
- drugs, eg NSAIDs (ibuprofen, gentomycin), or familial conditions causing vasculitis
POSTRENAL
- obstruction to urinary flow causing back up of pressure
- eg renal stones, enlarged prostate, foetus head
Risk factors for AKI
Age Drug use Hypertension Diabetes Chronic kidney disease
Complications of AKI
Hyperkalaemia - decreased kidney function, so less K⁺ secretion to tubular fluid, more in blood - TREAT ASAP, can induce arrhythmia and heart failure
Acidosis - less H⁺ excretion, so build up
Fluid overload - less fluid excretion
Uraemia - urea and other waste products build up in body, causing confusion, coma, pericarditis
CKD
Chronic kidney disease
= function of kidneys decreasing over years
- often progressive, need to know about even if currently asymptomatic, can reduce risk factors
- often asymptomatic - reduction in GFR from 90 to 45ml/min may not show symptoms, will only get noticed in bloods
Classification of CKD
Based on GFR
Class I - more than 90ml/min
etc
Class V - less than 15ml/min - end stage renal failure
Causes of CKD
Hypertension
Diabetes
Polycystic kidney disease - familial, so cause of CKD in the young
Symptoms of CKD
Nausea & vomiting
Itching
Swelling - due to decreased water excretion
Lethargy - anaemia, as less EPO
- often asymptomatic up to stage III (30-60ml/min)
Complications of CKD
Anaemia
Renal bone and mineral disease - less calcitriol produced, PTH released to strip bones of calcium. Weakened bones more risk of fracture
Hypertension - altered RAAS, increase bp, kidneys ‘think’ problem is due to decreased blood flow, so increase bp
End stage renal failure - GFR less than 7ml/min, need dialysis/transplant
AKI vs CKD
Both increase plasma creatinine, K⁺ and urea - decrease in kidney function so decrease excretion
CKD
- long term endocrine changes once stores of EPO and calcitriol have been used up - present as anaemia and hyperparathyroidism
- > long term fibrosis and atrophy -> shrivelled kidneys on ultrasound
HYPERKALAEMIA PRIMARY CONCERN
Conservative (non-dialytic) kidney management
Where would normally be starting dialysis, but choose not to
Palliative care, to manage symptoms
Haemodialysis
4 hours at a time, 3x per week (forever)
At hospital or dialysis unit, or can be at home - better if more regular
Diffusion and hydrostatic ultrafiltration - pressurised to force water across into dialysate, carrying small ‘dirty’ molecules with it
- has heparin to stop clotting, air traps to stop air into veins
- create fistulas and grafts to give access - arterialise veins to get better pressure
Advantages of haemodialysis
Intermittent - don’t need to worry most of time
Effective - gives 10% extra kidney function
Passive - not patient involved
Disadvantages of haemodialysis
Vascular access
Cardiovascular instability - taking fluid away, but then allows to build up
Expensive - £25,000 per patient per year
Less flexible - far to travel, can’t be rearranged
Complications of haemodialysis
Uraemia
Access related infections
Hyperkalaemia -> fluid overload, heart failure
Amyloid - big molecules build up
Peritoneal dialysis
4 times daily
At home, can be overnight
Tube in peritoneal cavity all the time - flush out from peritoneal cavity, then replace
Takes advantage of existing semipermeable membrane - peritoneal lining
Uses diffusion and osmotic ultrafiltration - can’t change pressure in abdomen. Add in osmotically active solute, eg glucose. Creates osmotic gradient, sugar sucks fluid out of blood (can’t be left too long)
CAPD (continuous ambulatory PD) or APD (automatic PD) - left for around 8 hours each night
Advantages of peritoneal dialysis
Gives independence
No vascular access
Less expensive - £18,000 per patient per year
Greater diet/fluid freedom
Disadvantages of peritoneal dialysis
Less efficient
Peritonitis - infection from tube, painful
Limited life span
Complications of peritoneal dialysis
Uraemia (CV risk)
PD peritonitis
Amyloid - big molecules build up
Renal transplant
BEST OUTCOMES
Plumbed in via groin, never leg now, as easier to plumb ureter into bladder
Leave old kidneys in
Living donor - 35% - related/spouse/friend/altruistic - outcomes better
Deceased donor - 65% - DCD (cardiac death) or DBD (brain death)
VERY cost effective
Risks to living donor
Death, major complications
Infection
Kidney function ~ halved - ok if old but hard to predict future kidney profile if young, bar set higher
Suitable living donor
Understands risks Blood group and tissue type compatible No risk of kidney disease Medically and psychologically fit No conditions that would be transmitted with kidney - cancers, infections
Assessed with ultrasound, kidney function, CT
Tissue type matching
0: 0:0 perfect match
2: 2:2 no matches
1: 1:1 1 match at each - still can use
