Kidneys Flashcards
Describe the surface anatomy of the kidneys
Between vertebral levels T11-L2/3, the right is lower and the hila sit around L1
Sit under 12th rib with the left under 11th & 12th rib
What is the renal angle?
Between 12th rib and lateral border of vertebral column extensor muscles
Describe the surface anatomy of the ureters
Run vertically inferior to pelvic cavity; follow tips of lumbar vertebrae
transverse processes
What protective layers cover the kidneys?
Perinephric fat
Renal fascia
Paranephric fat
Psoas fascia
Renal fascia is loose & kidneys can move with body position. What occurs if they move too much? And what can be a sign of this?
Nephroptosis
Blood in urine when running
What tissue type do kidneys derive from?
Metanephros - mesoderm
Ureteric bud
What can happen if the ureteric bud develops abnormally?
Bifid Ureter
Duplicated ureter
Absent
During what time frame do the kidneys ascend to their adult position?
Week 6-9
Start in pelvic cavity
Migrate superiorly
Receive new blood supply as they move upwards and take the ureters with them
What is a pelvic kidney?
One kidney never migrates and so remains in the pelvic cavity
If there is no impingement then it doesn’t matter
What is a horseshoe kidney?
Two kidneys fused and not ascended. Gets stuck on IMA, can block it so ischemic bowel
What is a polar renal artery?
Artery not running into hilum. Squash ureter so renal pelvis enlarges
What is the allantois?
Passes from cloaca to umbilicus
What is the adult remnant of the allantois?
Urachus
Name 3 remnants of the allantois that can cause clinical problems
Urachal fistula/patent - urine can leak out
Urachal cyst - can get infected
Urachal sinus - blind ended tract from umbilicus, cheesy discharge
Describe the blood supply to the kidneys
Renal arteries at L1/2 (listen for bruits)
Run posterior to renal vein & IVC
Segmental supply (4/5 end arteries)
Describe venous drainage of the kidneys
Right renal vein directly join IVC
Left veins receive gonadal & suprarenal veins
Left renal vein runs under SMA to join IVC
Describe nerve supply to the supra renal glands
Preganglionic sympathetic fibres (T10-L1)
Synapse directly with chromaffin cells in medulla
What arteries do the ureters receive blood supply from?
Renal Gonadal Aortic Internal iliac Vesical/prostatic
Which direction should the ureters be displaced in order to prevent disrupting their blood supply?
Displace ureter medially in abdo cavity
Displace ureter laterally in pelvic cavity
What pain pattern occurs with renal calculi?
Shifting loin to groin pain T12-L1/2
What is the main differential concern for an elderly patient presenting with presumed left sided renal colic?
Dissecting aortic aneurysm
What are potential sites for stones?
Renal tract (urolithiasis) Gallbladder/biliary tree (cholelithiasis) Salivary glands (sialolithiasis) Appendix (faecolith) Prostate Veins (phleboliths)
How do stones form?
Increased concentration of solutes causing supersaturated solution
Stasis
Infection
What effects can stones have?
Block ducts: colic, jaundice, renal failure
Chronic inflammation: Cholecystits, cystitis, sialadenitis
Infection
Describe salivary stones
Occur more in females Usually Wharton’s duct Pain and swelling of gland Idiopathic, infection, drugs Remove stone – open/endoscopic
Describe gallstones
Common (10%), more in females
GB stores & concentrates bile
Most stones cholesterol based due to high fat diets/hypercholesterolaemia
Pigment stones found in haemolytic disorders (high serum bilirubin)
Ratio of cholesterol:bile salts & lecithin
How do gallstones present?
Asymptomatic
Abdominal pain
Jaundice
Fever
How do you investigate gallstones?
Bloods – LFT, amylase
USS
ERCP (endoscopic retrograde cholangio pancreatography)/MRCP
Describe what factors can affect the likelihood of developing renal stones
Common (10%) Males > females
Varies with geography/climate
Age, Peak onset 20-30
Fluid intake, Family history, Affluence/diet/BMI
Describe how renal stones form pathophysiologically
Urine normally supersaturated but metastable
Crystal growth more than normal
Crystals aggregate to form small stones
Symptomatic stones require particle retention to enlarge
What different types of renal stones can form?
Ca oxalate 60% - visible on xray Ca phosphate 20% - visible on xray Urate 7% - not visible on xray, but will show on USS and CT Struvite 7% Cysteine 2% Others
Where do renal stones get stuck?
Pelvic ureteric junction (PUJ)
Pelvic brim
Vesicoureteric junction (VUJ)
Bladder urethra outlet
What can cause calcium oxalate stones to form?
Hypercalciuria: Idiopathic, Rare genetic disorders,Hyperparathyroidism, Malignancy, Sarcoidosis/TB
Hyperoxaluria: Primary hyperoxaluria, Secondary- Dietary, Enteric
Describe struvite stones
Triple phosphate
Urinary infection by urea-splitting bacteria (split urea to CO2 and ammonia) so alkaline urine
Proteus mirabilis, Klebsiella, Pseudomonas, Providentia
Even low colony numbers produce urease
Struvite stones cause most staghorn calculi
Describe the 2 types of staghorn calculi
Struvite stones cause most staghorn calculi
Partial staghorn – renal pelvis stone extending into at least 2 calyceal groups
Complete staghorn – renal pelvis stone extending into all major calyceal groups filling at least 80% of collecting system
What are risk factors for struvite stones?
Risk factors all related to UTIs Female Indwelling catheters Neurogenic bladders Urinary tract abnormalities Stagnant urine
Describe the formation of cysteine stones
Autosomal recessive disorder affecting dibasic amino acid transporter in tubule
Cystine not reabsorbed – crystalizes
Faintly radio-opaque, Often staghorn
Young, mulitple stones
5% get ESRF
Hard to manage; drink more, alkalinise urine
Describe uric acid stones
Purine metabolism Associated with metabolic syndrome and acidic urine Radiolucent Gout Some medications
How will a patient with renal stones present?
Loin to groin pain (renal colic), Can’t get comfortable, Radiates to testicle Haematuria Vomiting Irritative voiding symptoms Exclude leaking AAA
What history information do you need from someone presenting with renal stones?
No of stones passed Frequency of stone formation Age at first onset Kidney(s) involved Stone type Previous interventions
What initial investigations would you perform on someone presenting with renal stones?
Urine dipstick (haematuria, pH)
Serum creatinine/electrolytes, calcium, urate
Urine microscopy & culture
Imaging: Urgent, Immediate if fever - pyonephrosis
KUB- Sensitivity 50% Ca>struvite>cystine>urate, USS- Sensitivity 60% (80% for obstruction), CT KUB
What is the initial management of a patient with renal stones?
Infected obstructed kidney requires immediate drainage
Need to remove them if: Pain/failure to pass, Recurrent infection, Renal impairment, Bleeding, Some jobs (airline pilot)
How can renal stones be removed?
Fragmentation: Extracorporeal shockwave lithotripsy (ESWL), Focussed shockwave
Removal: PCNL Percutaneous nephrolithotomy, surgery, laser
What are complications of Extracorporeal shockwave lithotripsy (ESWL)?
Haematuria
UTI
Steinstrasse (stone fragments block ureter)
Tubular damage
What are the functions of the kidneys?
Removal of toxins Electrolyte balance Acid base regulation Fluid and volume regulation Endocrine functions
What cell types are found in the loop of Henle?
Thin - cuboid cells
Thick - columnar cells
What do cells in the distal convoluted tubule look like?
Virtually no brush border
Active cells with lots of cytoplasm
What type of cells are found in the ureters?
Transitional epithelium
Folded to allow stretch
Multiple layers for protection
Where do the kidneys sit in the abdomen?
Paired retroperitoneal organ located on posterior abdominal wall
Hilum at L1
What are the posterior relations of the kidneys?
Costodiaphragmatic recess
Quadratus lumborum
Psoas major
12th rib
What is the renal papilla?
Drainage point into calyxes
What is Psoas fascia?
Forms sheath down to hip region – infection can spread down this route; abscess can form under fascia
What is Thoracolumbar fascia?
Tough covering of intrinsic vertebral column muscles
What is Renal fascial space?
Communicates across midline, and serves as route for infection spread
What is nephroptosis?
Renal fascia is loose & kidneys can move with body position
Nephroptosis occurs if they move too much
What does the kidney develop from?
Metanephros (mesoderm) & ureteric bud
Describe the blood supply of the kidneys
Renal arteries at L1/2 (listen for bruits) behind IVC on right
Run posterior to renal vein & IVC
Segmental supply (4/5 end arteries)
Describe the venous drainage of the kidneys
Right renal vein directly join IVC
Left veins receive gonadal & suprarenal veins
Left renal vein runs under SMA to join IVC
Describe the blood supply to the supra renal glands
Left vein drains to renal vein
Right vein drains to inferior vena cava
Describe the nerve supply to the supra renal glands
Preganglionic sympathetic fibres (T10-L1)
Synapse directly with chromaffin cells in medulla
What do the ureters develop from?
Ureteric bud of mesonephric duct
Which arteries supply the ureters?
Renal Gonadal Aortic Internal iliac Vesical/prostatic
What is the main differential concern for an elderly patient presenting with presumed left sided renal colic?
Dissecting aortic aneurysm
Which sensory nerves are involved in renal calculi pain?
Renal plexus at renal pelvis Abdomino-aortic plexus at pelvic brim Hypogastric plexus (superior) at vesico ureteric junction
What do the ureters cross to enter the pelvic cavity?
Iliac vessels
How much of an adult male is water?
60% so in 70kg male, 42 Litres
What are the 2 main compartments of ECF?
Interstitial fluid which surrounds the cells
Plasma which is non-cellular component of blood
What differences exist between Interstitial fluid and plasma?
Proteins which remain in plasma
What is osmosis?
Net diffusion of water across a selectively permeable membrane from a region of high water concentration to a region of low water concentration
What are osmoles?
Number of osmotically active particles in a solution
What are the endocrine functions of the kidney?
Production of EPO
Alpha hydroxylase production for vit D activation
RAAS system
What is EPO?
Erythropoietin, produced by interstitial cells in cortex & outer medulla
Growth factor, stimulates production of RBC precursors in bone marrow
Stimulus for its release is hypoxia
Kidneys are major source, disease can therefore result in anaemia (normochromic normocytic)
What is the functional unit of the kidney?
Nephron
What are the 3 main processes performed by the nephron?
Filtration
Reabsorption
Secretion
What is urinary excretion rate?
Filtration rate + Secretion rate – Reabsorption rate
What is renal blood flow rate? And what is renal plasma rate?
1 litre per min renal blood flow
600ml per min renal plasma flow
What make up the layers of the glomerular filtration barrier?
Capillary endothelium (fenestrated) Basement membrane (negative charge) Epithelial cells (foot processes - podocytes & filtration slits)
How is the passage of substances limited across the glomerular filtration barrier?
By their size, shape and charge
What cells are excluded from glomerular filtrate?
Blood cells and plasma proteins
What effect do disease processes have on filtrate in the kidneys?
Alter the properties of barrier allowing protein to appear in the filtrate
What factors determine filtration?
Glomerular capillary filtration coefficient, Kf (leakiness of barrier)
Net filtration pressure (NFP)
GFR = Kf x NFP
What is glomerular filtration rate?
GFR
The volume of filtrate formed by all the nephrons in both kidneys per unit time
What is the glomerular filtration coefficient Kf?
Reflects:
Surface area available for filtration
Hydraulic conductivity (permeability) of the filtration barrier
How might Kf be affected in disease processes?
Reduced number of nephrons or processes which damage the filtration barrier will ↓surface area or ↓permeability & ∴decrease GFR
What is net filtration pressure?
Sum of pressures acting across the filtration barrier (Starling forces) Sum of the hydrostatic pressures
Sum of the colloid osmotic (oncotic) pressures
NFP = PG (glomerular hydrostatic) – PB (bowmanns capsule hydrostatic) – πG (glomerular colloid osmotic) + πB (bowmanns capsule colloid osmotic)
Typical is 10mmHg
What does glomerular hydrostatic pressure rely on?
Arterial pressure
Afferent arteriole resistance
Efferent arteriole resistance
How does most regulation of GFR occur?
Changes in glomerular hydrostatic pressure
How can you increase GFR?
Afferent arteriole dilation &/or Efferent Arteriole constriction
How can you decrease GFR?
Afferent Arteriole constriction &/or Efferent Arteriole dilation
What factors can cause Afferent Arteriole dilation and therefore lead to increased GFR?
Prostaglandins Kinins Dopamine low dose Atrial natriuretic peptide Nitrous oxide
What factors can cause Afferent Arteriole constriction and therefore lead to decreased GFR?
Angiotensin II high dose Noradrenaline Endothelin Adenosine Vasopressin
Describe the relationship between GFR and Arteriole resistance
Changes in AA resistance, effect on GFR is fairly linear
For EA resistance, effect on GFR is biphasic: Initial EA constriction causes ↑GFR by ↑glomerular hydrostatic pressure
Severe EA constriction slows down renal blood flow so that glomerular osmotic pressure rises more than hydrostatic & ∴GFR falls
What effect does angiotensin II have on GFR?
Preferentially constricts Efferent Arteriole – so increases glomerular hydrostatic pressure and therefore increases GFR
Which vasoactive substances dilate the Afferent Arteriole and therefore cause increased glomerular hydrostatic pressure and GFR?
Prostaglandins and atrial natriuretic peptide (ANP)
Which vasoactive substances constrict the Afferent Arteriole and therefore decrease glomerular hydrostatic pressure and GFR?
Noradrenaline (sympathetic nervous system), adenosine and endothelin
What occurs in the peritubular capillaries?
After leaving the glomerular capillaries and passing through the efferent arteriole the blood enters the peritubular capillaries
Changes in hydrostatic pressure and colloid osmotic pressure mean that absorption rather than filtration is favoured
Describe the autoregulation of GFR
GFR and renal blood flow relatively constant across a range of systemic blood pressures (~80–180 mm Hg)
Prevents large changes in renal excretion of water & solutes
Two mechanisms of autoregulation: Myogenic response and Tubuloglomerular feedback
What is Myogenic autoregulation of GFR?
Increase in arterial blood pressure
Increased renal blood flow and increased GFR
↑stretch of afferent arteriole smooth muscle which opens Ca channels Reflex contraction of AA smooth muscle, Vasoconstriction
↑Resistance to flow prevents changes in renal blood flow & GFR
What is a Myogenic response?
Inherent ability of smooth muscle in afferent arterioles to respond to
changes in vessel circumference by contracting or relaxing
What is the Tubuloglomerular feedback to maintain GFR when BP increases?
Mechanism links changes in [NaCl] in tubule lumen to control of afferent arteriole resistance
Utilises juxtaglomerular apparatus, Macula densa cells in initial part of
distal tubule sense [NaCl]
Arterial blood pressure increased, causes a transient ↑GFR which increases [NaCl] delivered to distal tubule
Release of paracrine factors (adenosine) by macula densa cells
Adenosine causes constriction of Afferent Arteriole smooth muscle
Vasoconstriction of AA so ↑Resistance to flow
Restores renal blood flow & GFR
What is the Tubuloglomerular feedback to maintain GFR when BP decreases?
Mechanism links changes in [NaCl] in tubule lumen to control of afferent arteriole resistance
Utilises juxtaglomerular apparatus, Macula densa cells in initial part of
distal tubule sense [NaCl]
Arterial blood pressure decreases, causes a transient ↓GFR which decreases [NaCl] delivered to distal tubule
Release of paracrine factors (renin) by macula densa cells
Renin causes release of Angiotensin II which causes constriction of Efferent Arteriole smooth muscle
Vasoconstriction of EA so ↑Hydrostatic pressure
Restores renal blood flow & GFR
What clinical disorders can occur if the kidneys dysfunction?
Failure of maintenance of fluid volume: Hypertension, Oedema
Failure of fluid composition: electrolyte and acid base disorders
Failure of excretion of waste: uraemia, drug toxicity
Failure of endocrine function: anaemia, renal bone disease
What investigations can be done relating to the kidneys? And what are you looking for?
Urine: What’s being filtered? What’s being excreted? e.g. protein, blood, glucose, leucocytes, osmolarity
Blood: Are waste products accumulating? Electrolyte abnormalities? Evidence of underlying cause? e.g. urea, creatinine, eGFR / GFR, sodium, potassium, pH, osmolarity, autoimmune diseases
Imaging: Any macroscopic structural abnormalities? Any functional abnormalities? e.g. ultrasound, plain X ray, CT, MRI, contrast studies, nuclear imaging
Biopsy: Any microscopic structural abnormalities?e.g. light microscopy, immunohistochemistry, electron microscopy
What are indicators of renal decline?
Proteinuria / albuminuria, Haematuria: Indicate damage
Estimated GFR / GFR, Serum creatinine /urea: Indicate function Calcium / phosphate homeostasis, Electrolytes /pH, Fluid balance / urine volume, Haemoglobin: Indicate function but not quantitative
What does proteinuria show about kidney function? And how can you detect it?
Indicates damage to the filtration barrier
Strong association between proteinuria and rate of disease progression in chronic kidney disease (CKD)
Can be detected by urine dipsticks
More sensitive methods include protein-creatinine ratio (PCR) and albumin creatinine ratio (ACR)
What is haematuria and what can effect its presence?
Blood can originate anywhere in urinary system
Beware menstrual bleeding and false positives on urine dipsticks e.g.
myoglobinuria
May be visible (frank / macroscopic) or non-visible (microscopic)
Age of patient an important factor in differential diagnosis
What is GFR?
Glomerular filtration rate (GFR)
The volume of filtrate formed by all the nephrons in both kidneys per unit time
What happens to GFR in disease states?
Directly related to function of nephrons & declines in all forms of progressive kidney diseases
What is the best overall index of kidney function in health &disease?
GFR
What is a normal GFR?
Linked to surface area of body ∴typical young male GFR = 120 ml/min/1.73m2
What factors effect the estimated GFR?
Age, sex and body size – declines with increasing age
What is renal clearance?
Volume of plasma from which a substance is completely cleared by the kidneys per unit time
Urine production x substance concentration in urine / substance concentration in plasma
Which substances have no renal clearance?
Proteins
Which substance is filtered and completely reabsorbed so has no renal clearance?
Glucose
Which substance is filtered but not reabsorbed or secreted and so gives an approximation of GFR?
Inulin
Which substance is filtered and partially reabsorbed?
Urea
Which substance is filtered and secreted?
Creatinine
For renal clearance of a substance to equal GFR, what properties must it have?
Freely filtered across the glomerulus Glomerulus only route of excretion Not reabsorbed or secreted Non-toxic Easily measured
What is creatinine and why is it used as an estimate for GFR?
Formed from breakdown of creatine, a skeletal muscle component
Produced at a steady rate for a given individual
Freely filtered at glomerulus & not reabsorbed
Small amount of secretion means clearance tends to overestimate GFR
Requires 24 hour urine collection – issues with compliance, time and reliability, Not suitable for a routine measure of renal function / GFR
Three tests used routinely to assess renal function, what are they?
Serum urea
Serum creatinine
Estimated GFR (eGFR)
Something normally filtered by kidneys builds up in the blood indicates ↓GFR and therefore ↓renal function
What is serum urea and what does it measure?
Nitrogen containing metabolic waste product of protein breakdown
Also known as: blood urea nitrogen (BUN)
Filtered but also partially reabsorbed
Levels typically rise in kidney disease as GFR falls
Serum levels reflect more than just GFR
What factors can increase serum urea?
Increase production: High protein diet, Increased catabolism (e.g.trauma, infection, surgery, cancer), Gastrointestinal bleed, Drugs e.g. corticosteroids, tetracyclines
Decreased elimination: Renal disease causing ↓GFR, Poor renal blood flow e.g.dehydration, hypotension
Why must a change in urea be compared to creatinine to see if there is a parallel change?
If both increased in parallel ie.both doubled, then a fall in GFR likely
If urea disproportionately higher than creatinine, need to consider:
Dehydration, High protein diet, GI bleed, Catabolic state
What factors can affect normal serum creatinine levels for that person?
Related to muscle mass: Age, sex, amputation, malnutrition, muscle wasting, ethnicity
Diet also affects creatinine levels (vegetarian diet vs. meat rich diet)
What happens to serum creatinine levels with diseased kidneys?
Increase as GFR is reduced
What happens to serum creatinine levels in a body builder with normal kidneys?
Levels will be high due to muscle mass and so will give impression of renal failure despite normal kidney function
What will serum creatinine levels be like in a elderly patient with diseased kidneys?
Levels may appear normal. Decreased GFR increases levels but decreased body mass decreases levels. Kidney disease may be masked and not detected
Why is serum creatinine not a useful measure in early kidney disease?
Can lose ~50% of renal function (GFR) and still appear to have a serum creatinine that lies within the ‘normal’ range
What is Estimated GFR (eGFR)?
Uses equations to calculate the GFR based on a single serum measurement of a substance
Incorporates clinical information along with a single serum measurement to generate an estimated GFR (eGFR)
Most use serum creatinine, age, sex and ethnicity to calculate
CKD-EPI equation (CKD Epidemiology) – recommended by NICE
Why do we need tubular processing?
Fine tune volume and composition of urine & to avoid huge fluid &
solute losses
Reabsorption more important than secretion for most substances
Describe the general mechanisms underlying tubular reabsorption
Utilises passive and active transport mechanisms to move fluid & solutes from tubule lumen to peritubular capillary
Luminal & basal surfaces of tubule epithelial cells have different transporters allowing concentration gradients to be established
Na+/K+ ATPase provides concentration gradient for reabsorption of many substances along the nephron
Water passively reabsorbed and linked closely to sodium reabsorption & permeability of the different parts of the nephron
Where does the majority of reabsorption occur?
Proximal convoluted tubule
Where does most fine tuning of solute concentrations occur?
Distal parts of nephron under hormonal control
How much urine is produced per day?
1.5 litres
Describe the function of the proximal convoluted tubule
Majority of sodium & water reabsorption occurs here
Brush border increases surface area
Mitochondria provide energy
Site of secretion of metabolic acids / bases, drugs etc.
Tubule fluid leaving PCT is isosmotic as epithelium is freely permeable to water
Essentially all glucose & amino acids reabsorbed
Co-transporters) linked to sodium reabsorption
Sodium glucose co-transporters (SGLT2 mainly) on luminal side move glucose against concentration gradient
Glucose transporters (GLUT) on basal side allow facilitated diffusion into interstitial fluid
Similar process for amino acids
Which glucose transporters are present in the proximal convoluted tubule?
Sodium glucose co-transporters (SGLT2 mainly) on luminal side move glucose against concentration gradient Glucose transporters (GLUT) on basal side allow facilitated diffusion into interstitial fluid
What can lead to loss of glucose in the urine?
There are a finite number of SGLT transporters on tubule cells
Work fine within normal physiological limits of plasma glucose
If amount of glucose in filtrate increases, eventually reach a
transport maximum (Tm) where reabsorption cannot go any faster
This leads to loss of glucose in urine
Water is also retained in the tubule lumen and excreted along with the
glucose
Describe the secretion of Na
Sodium reabsorption linked to secondary active transport of hydrogen ions into lumen (secretion)
Important for bicarbonate reabsorption
Na+/H+ exchanger, NHE (counter transporter)
What are the 3 parts of the loop of Henle?
Thin descending limb
Thin ascending limb
Thick ascending limb
Which part of the loop of Henle is permeable to water?
Thin descending limb
What occurs in the thin descending limb of the loop of Henle?
Permeable to water
No active reabsorption or secretion ofsolutes
What occurs in the thin ascending limb of the loop of Henle?
Impermeable towater
Essentially no active reabsorption or secretion of solutes
What occurs in the thick ascending limb of the loop of Henle?
Impermeable to water
Active reabsorption of sodium (~25% filtered load) & other solutes
Dilutes the luminal fluid (hypo-osmotic) as solutes are removed but water cannot follow
Reabsorption from tubule lumen mediated by sodium, potassium 2-chloride co-transporter (Na+K+2Cl-)
Positive charge in lumen encourages paracellular reabsorption of cations (including Ca2+ and Mg2+)
What occurs in the early distal convoluted tubule?
First portion contains the macula densa (sensitive to [NaCl]) part of juxtaglomerular apparatus involved with feedback control of GFR & blood pressure
Impermeable to water
Active reabsorption of sodium & water (~5% filtered load)
Sodium-chloride co-transporter on luminal side
Further dilutes the tubular lumen fluid
What occurs in the Late distal & cortical collecting tubule?
Water permeability of this part of nephron under hormonal control by antidiuretic hormone (ADH): Water permeable when ADH present, Water impermeable when ADH absent
What cell types are present in the cortical collecting duct?
Principal cells: sodium reabsorption & potassium secretion
Intercalated cells: potassium reabsorption & hydrogen ion secretion
What are the functions of principal cells?
Na enters principal cells via epithelial Na channels (ENaC) on luminal side
Transported out of cells by Na+/K+ ATPase to maintain concentration gradient
Number of ENaC channels & activity of ATPase under hormonal control
by aldosterone
Important site of regulation & fine tuning of sodium reabsorption & potassium secretion
Describe the Medullary collecting duct
Final site for urine processing, regulating urine concentration
Water permeability under hormonal control by ADH
Surrounded by medullary interstitium with high concentration of solutes
Urea permeability allows medullary interstitium to remain concentrated
What effect does aldosterone have on the kidneys?
Acts on collecting duct and tubule
Increases NaCl & H20 reabsorption
Increases K secretion
What effect does angiotensin II have on the kidneys?
Acts on proximal tubule, thick ascending limb, distal tubule and collecting duct
Increases NaCl & H2O reabsorption
Increases H secretion
What effect does ADH have on the kidneys?
Acts on distal tubule and collecting duct
Increases H2O reabsorption
What effect does atrial natriuretic peptide have on the kidneys?
Acts on distal tubule and collecting duct
Deceases NaCl reabsorption
What effect does parathyroid hormone have on the kidneys?
Acts on proximal tubule, thick ascending limb and distal tubule
Decreases PO4 reabsorption
Increases Ca reabsorption
What direct and indirect changes can receptors detect in the kidneys in regards to electrolyte balance?
Direct – [K+] has direct effect on release of aldosterone
Indirect – baroreceptors indicate ECF volume (marker of sodium)
Describe Na regulation by the kidneys
Major osmotically active extracellular electrolyte, major determinant of ECF volume
Kidneys help maintain ECF volume by regulating Na excreted in urine
Na is lost – water will be lost and ECF volume will fall (and vice versa)
Normally reabsorb ~99.6% sodium that is filtered i.e. only excrete small
amount of daily filtered load in urine
Regulated by local, hormonal & neural factors
Describe the role of the kidneys in Pressure diuresis / natriuresis
Ability of kidney to increase urine output / reduce sodium
reabsorption in response to increases in arterial blood pressure
Simple way of regulating extracellular volume / sodium
BP chronically elevated - mechanism even more sensitive
Maintain blood volume over a wide range of fluid (& sodium) intake
What is the function of the juxtaglomerular apparatus?
Secrete renin in response to falls in extracellular volume / low sodium
Falls in ECF volume detected by baroreceptors around the body
Aim of response is to increase sodium reabsorption and therefore ∴water reabsorption
What cells is the juxtaglomerular apparatus comprised of?
Macula densa cells
Extraglomerular mesangial cells
Granular cells (afferent arteriole)
What are the main triggers to renin release? And which cells release it?
Released by granular cells of afferent arteriole:
Low afferent arteriole pressure
Activation of sympathetic nerves that supply JGA
Low [NaCl] in distal tubule
All markers of fall in blood pressure / fall in ECF volume
Describe the RAAS system
Renin catalyses conversion of angiotensinogen to angiotensin I
Angiotensin converting enzyme (ACE) catalyses conversion of angiotensin I to angiotensin II
Angiotensin II causes release of aldosterone, vasoconstriction and Na and water reabsorption in the kidneys
Where is angiotensinogen produced?
Liver
Where is ACE produced?
Lungs
Where is aldosterone produced?
Adrenal gland
What is the function of the RAAS system?
Maintain extracellular volume and arterial pressure despite wide variations in dietary intake of sodium
Salt intake reduced leading to a fall in ECF volume – RAAS activity
increased
Salt intake increased leading to a rise in extracellular volume – RAAS activity reduced
RAAS also responds to situations where extracellular volume and
blood pressure falls independently of salt intake
Describe angiotensin II and its functions
Formed from enzymatic cleavage of angiotensin I by ACE
Powerful vasoconstrictor
Direct and indirect actions on to promote sodium and water reabsorption: Direct effect on renal tubule cells to increase Na reabsorption by increasing activity of Na transporters
Indirect effects include promotion of thirst, release of antidiuretic hormone (ADH) and aldosterone
Describe aldosterone and its functions
Increases Na reabsorption by its actions on principal cells in late distal / cortical collecting tubule
Secreted by adrenal cortex (zona glomerulosa) in response to increased angiotensin II or increased extracellular potassium concentration
Binds to intracellular mineralocorticoid receptors (MR)
Binds to nucleus & increases production of proteins, e.g. ENaC, Na+/K+ATPase, that increase ability of these cells to reabsorb sodium
What is atrial natriuretic peptide and its functions?
Hormone which inhibits sodium (and water) reabsorption by the kidney
Released by atrial muscle fibres in response to increased stretch of atria (as a result of excessive blood volume)
Causes small increases in GFR and decreases renal reabsorption
Levels can be raised in conditions where there is a pathological increase in extracellular volume e.g. cardiac failure
Describe the importance of potassium regulation by the kidneys
Extracellular concentration of K tightly regulated as it is a major determinant of resting membrane potential – small changes can result in cardiac arrhythmias
Most potassium (98%) is located in intracellular compartment
Need rapid ways to regulate extracellular levels
Balancing overall intake and output is mainly done by the kidneys
Short term control of potassium levels can be achieved by moving
potassium between intracellular & extracellular compartments
Note: serum [K+] is not necessarily a good reflection of total body
potassium
What factors shift K into cells and therefore decease extracellular K?
Na+/K+ ATPase activity: encourage cellular uptake of K with insulin (emergency treatment of hyperkalaemia)
Aldosterone: urinary excretion of potassium
Alkalosis (low extracellular [H+]) due to exchange of intracellular H+ for
extracellular K+
B adrenergic stimulation
What factors shift K out of cells and therefore increase extracellar K?
Insulin deficiency, diabetes
Aldosterone deficiency, Addison’s disease
B adrenergic blockade
Acidosis: high extracellular [H+] due toexchange of extracellular H+ for
intracellular K+
Cell lysis: release of intracellular K from damaged cell membrane
Strenuous exercise
Increased extracellular fluid osmolarity: cellular dehydration. Increases intracellular [K+] and results in a larger concentration gradient to promote movement out of the cell
Where is the majority of renal potassium excretion in the kidneys?
Secretion in late distal tubule / cortical collecting tubule
What factors determine the rate of K+secretion?
Activity of Na+/K+ ATPase
[K+] gradient between blood, principal cell & lumen
Permeability of luminal membrane to K+
What channels are involved in K excretion?
Na+/K+ ATPase moves K+ into principal cells creating a high
intracellular concentration
K+ passes through channels in luminal membrane into tubular lumen
Which cells other than principal cells can reabsorb K during depletion?
Intercalated cells
What factors regulate K secretion?
Plasma potassium concentration
Aldosterone
Tubular flow rate
H+ concentration
What effect does an increasing plasma K level have on rate of K excretion?
Increased Na K ATPase activity
Increased K gradient from blood to lumen
Increased aldosterone release
What effect does aldosterone have on K excretion?
Increased rate of potassium excretion
Due to increased NaKATPase activity and increased permeability of luminal membrane to K
What is aldosterone release controlled by?
Plasma potassium levels
What effect does increased tubular flor rate have on potassium levels?
Increased potassium excretion due to increased concentration gradient from principal cell to lumen
What factors can increase tubular flow rate?
Volume expansion
High sodium intake
Diuretics
What effect does increased H have on potassium levels?
Deceased rate of potassium excretion due to decreased NaKATPase activity
What factors cause K increased excretion?
Insulin Adrenaline Aldosterone ADH Plasma K levels
What is the Normal range for extracellular [K+]?
3.5-5.3 mmol/L
What are causes of hypokalaemia?
Reduced intake
Excessive losses e.g. diuretics, severe diarrhoea, aldosterone excess Altered body distribution
What are symptoms of hypokalaemia?
Often asymptomatic
Muscle weakness
Cardiac arrhythmias
What treatment is used in hypokalaemia?
Address underlying cause
Potassium supplementation
What can cause Hyperkalaemia?
Excessive intake
Inadequate losses e.g. acute kidney injury, aldosterone deficiency Altered body distribution e.g. acidosis
What are symptoms of Hyperkalaemia?
Often asymptomatic
Cardiac arrhythmias – ECG characteristic features e.g. tall T waves
What is treatment for Hyperkalaemia?
Address underlying cause Restrict intake Calcium gluconate (to stabilise myocardium) Insulin (along with glucose) to drive potassium into cells Aid excretion – fluids, ion-exchange resins, dialysis
What are the kidneys 2 roles in calcium and phosphate homeostasis?
Responding to PTH to increase calcium and decrease phosphate reabsorption
Activating vitamin D to enhance calcium absorption from GI tract
Which part of kidney reabsorption of calcium is enhanced by PTH?
Distal tubule
Why do patients with kidney disease get bone problems?
Kidney produces 1α-hydroxylase which converts inactive precursor into the active form of vitamin D
Develop renal bone disease due to failure to produce this enzyme so inability to absorb adequate calcium from diet
What absorbs phosphate in the GI tract?
Sodium phosphate co-transporter which usually reaches Tm from dietary phosphate so excess phosphate spills over into urine
What factors inhibit the sodium phosphate co transporter in the GI tract?
PTH & fibroblast growth factor-23 (FGF-23) inhibit the sodium phosphate co-transporter, thus reducing phosphate reabsorption
What is the net effect of PTH?
Increase calcium and reduce phosphate reabsorption
What can be consequences of fluid overload?
Oedema
Congestive heart failure - pulmonary oedema
Hypertension
What are clinical features of hypovolaemia?
Thirst Dizziness on standing Confusion Low JVP Postural hypotension Weight loss Dry mouth Reduced skin turgor Reduced urine output
What are clinical features of hypervolaemia?
Ankle swelling Breathlessness, pulmonary oedema (crackles) Raised JVP Oedema Weight gain Hypertension
What will a hypertonic solution cause a cell to do?
Shrink
Where can total body water be lost from?
Lungs
Skin
Faeces
Urine
What is the minimum fluid loss per day and therefore how much must we drink per day?
Total min. loss each day ~ 1400ml
Must drink >500ml
What is the obligatory urine volume per day?
500ml
How much is maximum urine production per day?
20 litres
How much is normal urine production per day?
1500ml
What is the normal urinary rate per minute?
1ml/min
How do you calculate Osmoles excreted/day?
Urine osmolality (Osm/kg) x urine output (L/day)
How much solute volume is excreted per day?
Average excretion 600 mOsm solutes/day
In 1500 ml urine, urine osmolality is 400 mOsm/kg (600 = 400 x 1.5)
If 3000ml urine, urine osmolality is 200 mOsm/kg (600 = 200 x 3)
What is Maximum urine osmolality?
1200 mosmol/kg H2O
What fluid balance issue is caused by diabetes?
High levels of solute cause a diuresis even if high levels of ADH present
What is Polyuria?
High urine flow
What can cause increase in solute excretion in the urine? And therefore an osmotic dieresis?
Glycosuria (diabetes mellitus)
Diuretics (failure to reabsorb sodium)
What can cause an increase in water excretion?
Excessive water ingestion
Inability to concentrate urine (tubular damage, diabetes insipidus)
What is oliguria?
Reduced urine volume
What can cause oliguria?
Poor perfusion (dehydration / reduced volume)
Where does most water reabsorption occur in the nephron?
Proximal convoluted tubule
Describe Water reabsorption from collecting duct of nephron
Water reabsorption from collecting ducts is passive and requires:
Insertion of water channels (aquaporins), Regulated by ADH, release stimulated by: Cellular dehydration (increased plasma osmolality), Extracellular dehydration (decreased fluid volume)
An osmotic gradient: Generated by the countercurrent system
Where is ADH produced?
Supraoptic & paraventricular nuclei of hypothalamus
What is ADH?
Vasopressin
9 amino acid peptide
Where is ADH transported too from the hypothalamus?
Transported to posterior pituitary (cleavage of precursor)
Packaged into storage granules
Released by exocytosis
Plasma half life 10-15 mins
What are the two main functions of ADH?
Reduce water excretion
Stimulate vasoconstriction
What are stimuli for ADH release?
Raised plasma osmolality (hypertonicity)
Extracellular volume reduction
Angiotensin II (released if low BP/blood volume)
Nausea (precaution for expected vomiting and fluid loss)
Drugs e.g. nicotine & morphine
Which cells can influence the release of ADH?
Osmoreceptors in hypothalamus detect cellular dehydration
Peripheral volume receptors: Low pressure sensors in atria, pulmonary
vasculature, High pressure sensors in carotid sinuses & aortic arch, Stretch receptors in afferent arterioles (via release of Ang II)
Cause an increase in thirst and ADH release
Describe the process of restoring water balance from a low level
Water deficit -> increased osmolarity detected by osmoreceptors -> increased ADH secretion -> increased H2O permeability in distal tubule and collecting duct -> increased H2O reabsorption -> water volume restored
What is thirst?
Conscious desire for water
Where are thirst centres?
Hypothalamus
What inhibits ADH release?
Reduction in plasma osmolality (hypotonicity)
Extracellular volume increase
Drugs e.g. alcohol
Describe the cellular action of ADH
Binds to GPCR receptor which causes production of cAMP via Gs
This activates PKA which phosphorylates proteins
This leads to increased production of aquaporins and increased insertion of stored channels from vesicles into membrane thus increasing the permeability of the collecting duct to water
Where are different aquaporins located?
AQP1: widely distributed (permeability of PT)
AQP2: collecting duct (apical membrane, uptake from lumen) regulated by ADH
AQP3+4: collecting duct (basolateral membrane) allows H2O reabsorbed from the lumen to enter interstitium
AQP5: primarily non-renal (brain, lungs, salivary glands)
How can we form dilute urine?
Ascending limb of loop of Henle, tubule is relatively impermeable to
water in absence of ADH
Pumps move solutes out of tubule lumen, leave behind dilute tubular fluid which leads to dilute urine
How can we form concentrated urine?
Distal & collecting tubules/ducts permeable to water in presence of ADH, water moves so osmotic equilibrium with surrounding interstitium which leads to concentrated urine
Note osmolality of medullary intersitium ~1200mOsm/kg/H2O
What does ADH induced water movement require?
Osmotic gradient
What does the Osmotic potential of kidney interstitium depend on?
Urea and NaCl
Describe how the re circulation of urea contributes to our ability to concentrate urine
Filtered urea is recirculated & due to differing permeability along nephron becomes trapped at high concentration within medullary interstitium
Urea makes a key contribution to osmotic gradient
High protein diet improves ability to form a concentrated urine
What does the countercurrent mechanism rely on?
Loop of Henle
Vasa recta
What does the countercurrent mechanism result in?
A dilute filtrate entering distal nephron (allows water to move out of tubule to circulation by osmosis)
Generates an increase in [NaCl] in medulla, so contributing to increase in osmotic gradient (which allows osmosis of water)
Describe water and NaCl permeability changes through loop of Henle
Thin descending: Permeable to H2O, Na+, Cl- (passive)
Thin ascending: Impermeable to H2O, Minimal Na+, Cl-
Thick ascending: Impermeable to H2O, Na+, Cl- reabsorption (active)
What allows NaCl transport in the loop of Henle?
Na+, K+, 2Cl- (co-transporter) on luminal membrane driven by gradient generated by the Na+/K+-ATPase on basolateral membrane
Describe what NaCl and water movement occurs in the thick ascending limb
Reabsorption from tubule lumen mediated by sodium, potassium 2-chloride co-transporter(Na+K+2Cl-)
Positive charge in lumen encourages paracellular reabsorption of cations (including Ca2+ and Mg2+)
As water cannot follow, the remaining tubular lumen fluid is diluted
Describe countercurrent multiplication
NaCl pumps in thick ascending limb maintain 200 mOsmol difference to medullary intersitium
Water loss from thin descending limb to maintain osmolarity of medulla
Interstitial osmolarity always same as that in descending loop
Difference in osmolarities between descending and ascending limbs at any transverse level is only 200 mosmol/kg H2O
What is the role of the vasa recta in countercurrent multiplication?
For countercurrent to work, salt released from loop of Henle must
remain in medulla, while most of water is removed
Vasa Recta are long thinned walled blood vessels that parallel loops of Henle - hairpin arrangement
Low blood flow ~5-10% renal blood flow (enough to provide nutrients) Hairpin arrangement allows nutrient delivery & water removal while minimising disruption to medullary concentration gradient
Constant flow urea and NaCl stops precipitation
What are the consequences of countercurrent multiplication?
Filtrate hypo-osmotic relative to interstitium, water leaves by osmosis down a concentration gradient
Give 2 examples of Disorders of water regulation
Too much ADH: Syndrome of inappropriate ADH (SIADH)
Too little ADH: Diabetes insipidus (cranial or nephrogenic)
What is syndrome of inappropriate ADH? And what can cause it?
Excess ADH production
Causes: pneumonia, small-cell lung carcinoma, drugs, meningitis
Effects: Inappropriate water reabsorption leading to: Low plasma osmolality, Low serum [Na] (dilutional hyponatraemia), cerebral oedema, Urine inappropriately concentrated & high urinary [Na]
What are treatment options for syndrome of inappropriate ADH?
Identify & treat underlying cause
Restrict fluid intake
Drugs that inhibit ADH e.g. demeclocycline or vasopressin V2 antagonists e.g. tolvaptan)
Avoid correcting hyponatraemia with saline infusions
What is diabetes insipidus?
Inability to reabsorb water from distal nephron due to inadequate production (cranial DI) of ADH or insensitivity (nephrogenic DI) to ADH
What can cause diabetes insipidus?
Cranial DI (fail to produce/secrete ADH from hypothalamus/pituitary): head trauma, neurosurgery, tumours, infections Nephrogenic DI (renal tubules insensitive to circulating ADH): drugs (e.g. lithium), electrolyte abnormalities (↑[Ca2+]; ↓[K+])
What are the effects of diabetes insipidus?
Large losses of water in urine: Polyuria (10-15 litres/day)
Thirst & polydipsia (need access to fluids to keep pace with losses)
Low urine osmolality (dilute)
High / high normal plasma osmolality & serum [Na]
What investigations can be done to confirm diagnosis of diabetes insipidus?
Water/fluid deprivation test
Deprived of fluid so↑plasma osmolality should prompt release of ADH & concentration of urine if normal
Monitor plasma & urine osmolality, weight, BP
1st stage identifies if DI, 2nd stage differentiates cranial from nephrogenic. Administer synthetic ADH (desmopressin) to differentiate
What is treatment for diabetes insipidus?
Identify & treat underlying cause
Ensure adequate fluid intake to match losses
Synthetic ADH (desmopressin) – cranial DI
Drugs to sensitise renal tubules to ADH – nephrogenic DI
Why are the kidneys susceptible to drug induced acute kidney injury?
Highly vascular
Large surface area for binding & transport into blood
Reabsorption of water from kidneys concentrates drugs in nephron
What is the important factor with drugs if the kidney is not functioning properly?
Accumulate to toxic levels if excreted through kidneys and renal function is impaired
Which drugs should be avoided in renal disease?
Nephrotoxic drugs: consequences likely to be more serious when renal reserve is already reduced
Amoxicillin, ACE inhibitors, NSAIDs
What are reasons for problems with medications in patients with impaired renal function?
Failure to excrete drug or metabolites:mreduce dose / frequency, Consider alternatives
Side-effects poorly tolerated by patients (e.g. increased potassium)
Drugs less effective when renal function is reduced (e.g. diuretics)
What are dose adjustments in renal disease patients based on?
Severity of renal impairment
Proportion of drug eliminated by renal excretion
Toxicity of drug / ‘safety margin’
What does the BNF say about drug dosing in renal disease patients?
Use eGFR values to guide, recognise limitations & situations where dosing needs more accurate measures of GFR e.g.
Toxic drugs
Patients at extremes of weight
How does dialysis affect the analysis of dosing of patients with renal disease?
Some drugs removed by dialysis
Loss of therapeutic effect for some drugs
No longer worried about nephrotoxic effects
What effect does urine pH have on drug excretion?
Alkaline urine, acidic drugs more readily ionised
Acidic urine, alkaline drugs more readily ionised
Ionised substances (polar) more soluble in water – easier to excrete via kidneys
How can aspirin poisoning be rectified?
Aspirin is weak acid. Give them IV sodium bicarbonate so they excrete aspirin more quickly
What is diuresis?
Formation of urine by the kidney
What is a diuretic?
Substance that promotes the formation (excretion) of urine
What is natriuresis?
Renal excretion of sodium
What is a natriuretic?
Substance that promotes renal excretion of sodium
What are diuretics used for?
Treat fluid overload: oedema, CHF, hypertension
What are the 3 important and common classes of diuretics?
Loop diuretics
Thiazide diuretics
Potassium sparing diuretics
What is Tolvaptan?
ADH antagonist
Licensed for use in SIADH they produce a water diuresis, as opposed to a natriuresis – important as have dilutional hyponatraemia
Where do carbonic anhydrase inhibitors exert their effects?
Proximal convoluted tubule
Which drugs exert their effects in the proximal convoluted tubule and descending limb of loop of Henle?
Osmotic diuretics
Where do loop diuretics exert their effect?
Thick ascending limb of loop of Henle
What is the mechanism of action of loop diuretics?
Block apical Na+K+2Cl- transporters
Where do thiazide diuretics exert their effects and what is their mechanism of action?
Early distal convoluted tubule
Block apical Na+Cl- channels
Which part of the nephron is sensitive to aldosterone?
Late distal convoluted tubule, early collecting duct
What is spironalactone?
Aldosterone receptor blocker
What is amiloride?
ENaC antagonist
Which are the K sparing diuretics?
Spironalactone - aldosterone antagonist
Amiloride - ENaC antagonist
Give an example of a carbonic anhydrase inhibitor and describe how it exerts its effect
Acetazolamide
Weak diuretic, Inhibits carbonic anhydrase in proximal tubule
CO2 + H2O -> H2CO3 -> H+ + HCO3-
HCO3- can’t be directly transported from lumen – needs carbonic
anhydrase (CA) & secreted H+
When CA is inhibited, HCO3- reabsorption is blocked, along with Na+ & accompanying water
What can be a side effect of carbonic anhydrase inhibitors?
Prevents exchange and secretion of H+
Side effect can be metabolic acidosis
What are uses of carbonic anhydrase inhibitors?
Not usually prescribed for diuretic effect
Reduce intraocular pressure (aqueous humour production requires HCO3- secretion): glaucoma, eye surgery
Mountain sickness
Given orally or intravenously
Describe how osmotic diuretics work
Increase osmolality of filtrate: prevent water reabsorption
Act best where most osmotic reabsorption occurs (PT, descending loop of Henle)
Name 2 osmotic diuretics and describe their use
Mannitol: ↓ intracranial pressure,↓ intraocular pressure (glaucoma)
Glucose (natural): Filtered and reabsorbed by transporters: if Tm exceeded (e.g. uncontrolled diabetes mellitus) glucose excreted in urine -> polyuria (->polydipsia)
What is furosemide?
Loop diuretic
Which are the most powerful diuretics?
Loop diuretics
How do loop diuretics work?
↓ NaCl reabsorption in thick ALH causes ↓osmotic concentration in
medulla (so ↓ADH mediated H2O absorption)
Increase delivery of NaCl to distal collecting duct causes increased Na+ uptake there, so loss of K+ (& H+) - hypokalaemia
Why are loop diuretics effective in renal disease patients? But less effective in nephrotic syndrome?
Bind plasma proteins so not filtered, secreted directly into PT nephron Effective in renal impairment Nephrotic syndrome (large amounts of albuminuria) - bind to albumin in filtrate – may be less effective
What are the main uses of loop diuretics?
Peripheral oedema in chronic heart failure
Acute pulmonary oedema
Resistant hypertension
What are side effects of loop diuretics?
Increased frequency of urination Hypovolaemia & hypotension (excessive Na+ and water loss) Hypokalaemia Metabolic alkalosis can occur Ototoxicity (high doses)
Give examples of thiazide diuretics
Bendroflumethiazide, indapamide, chlortalidone
Describe the pharmacodynamics of thiazide diuretics
Weak/moderate diuresis (well tolerated), Usually given orally
Slower acting, but longer lasting than loop diuretics
Not so good in renal impairment (filtered and secreted)
Reduces calcium excretion in urine
What are the main uses of thiazide diuretics?
Hypertension
Peripheral oedema in chronic heart failure
Reduces calcium excretion i.e. lower Ca2+ in urine so may see used to treat hypercalciuria
What are side effects of thiazide diuretics?
Increased frequency of urination
Hypokalaemia / hyponatraemia / (metabolic alkalosis)
↑ plasma uric acid (gout) as it competes for uric acid transporter
Erectile dysfunction
Hyperglycaemia
Why do thiazide and loop diuretics cause hypokalaemia?
Increase delivery of NaCl to distal nephron & decrease blood volume
Increases potassium secretion by:
Increasing tubular flow rate
↑activity of Na+/K+ATPase via↑[Na+] & activation of RAAS
(↑aldosterone)
Intercalated cells also stimulated to secrete H+ hence alkalosis
Describe how potassium sparing diuretics work
Act on principal cells in late distal / cortical collecting tubule
Either inhibit ENaC or the mineralocorticoid receptor (MR)
Reduce K+ secretion
How do ENaC antagonists work as diuretics?
Blocks epithelial sodium channels (competes for Na+ binding site) & decreases luminal permeability to sodium
Weak diuretic alone
Used in combination with thiazide or loop diuretics
Reduced potassium secretion into lumen ∴ potassium retained
Describe how aldosterone antagonists work as diuretics
Aldosterone antagonist binds to mineralocorticoid receptor (MR)
Given orally and metabolised to active metabolite canrenone
Weak diuretic if used alone
Prevents synthesis of ENaC & Na+/K+ATPase activation & so reduced potassium secretion into lumen ∴ potassium retained
What are the main uses of aldosterone antagonists?
Chronic heart failure
Peripheral oedema & ascites caused by cirrhosis
Resistant hypertension
Primary hyperaldosteronism (Conn’s syndrome)
Used in combination, prevent K+ loss from loop / thiazide diuretics
What are side effects of potassium sparing diuretics?
Hyperkalaemia (care if prescribing with other agents that inhibit RAAS)
Gynaecomastia (aldosterone antagonists)
What is Aliskiren?
Renin inhibitor
What is Ramipril?
ACE inhibitor
What are ARBs?
Angiotensin II receptor blocker /antagonist
Eg losartan
What happens if thiazides and loop diuretics are combined?
Loop diuretics increase NaCl to distal nephron, increases efficiency of thiazides
Can cause large volume losses and K+ loss
What effects occur if loop or thiazide diuretics are combined with K sparing diuretics?
Get good diuretic function without loss of K+
Take care with K+ retention
What helps to determine GFR?
Balance of afferent (AA) and efferent arteriole (EA) resistances
What effects do NSAIDs have on GFR?
NSAIDs inhibit prostaglandins which normally cause dilatation afferent arteriole flow
NSAIDs↓in GFR
What effects do ACE inhibitors and ARBs have on GFR? So why are they used in CKD?
ACEI / ARB cause efferent arteriolar dilatation so↓in GFR
Initial fall in GFR but stabilises & renal function conserved long-term
In which renal condition should ACE inhibitors not be given?
Renal artery stenosis
ACE inhibitors will precipitate a continuing fall
What are the functions of the kidney?
Homeotasis: Fluid, electrolytes and acid base balance
Hormone production: Renin / angiotensin, Vitamin D metabolites, Erythropoietin
Excretion of metabolites: Organic acids, Phosphates, Urea / creatinine
What is the RIFLE criteria?
Risk: 1.5x↑ creatinine,↓ 25% GFR, 4 weeks
ESRD (established renal disease): Need RRT for>3 months
What is the AKIN criteria?
Stage 1: 1.5-2x ↑creatinine, 3x ↑ creatinine, <0.3ml/kg urine for 24h or anuria for 12h
What is the definition of acute kidney injury?
Significant deterioration in renal function, potentially reversible, over a period of hours or days
Where can the causes of acute kidney injury come from?
Pre-renal failure: Renal hypoperfusion, Systemic hypotension (Hypovolaemia, Sepsis), Renal artery stenosis, Drugs- ACE inhibitors, NSAIDs
Intrinsic renal failure
Post-renal failure: obstruction
How would you diagnose obstruction causing post renal failure?
Ultrasound scan
Anatomically: Where? In lumen, wall, Outside wall
What are the categories of intrinsic renal failure?
Primary renal disease: Glomerulonephritis
Secondary renal disease: Diabetes, SLE, myeloma
Interstitial nephritis: Usually caused by drugs
Secondary acute tubular necrosis: Established after pre-renal failure
What are the most common causes of acute kidney injury?
Pre-renal failure 85%: Hypoperfusion
Intrinsic renal failure 5%: Many causes, ATN
Post-renal failure 10%: Obstruction
What is important in a history for renal issues?
Rate of onset Precipitating factors Urinary symptoms Chronic symptoms Systemic features of autoimmune disease: Myalgias, rash, ENT symptoms, haemoptysis Relevant PMH/FH CKD, DM, vascular disease Drug history
What are important features to look for on examination with renal issues?
Fluid status: Tissue turgor, Mucous membranes/tongue, Pulse rate, rhythm and volume, Lying and standing blood pressure, JVP, Peripheral perfusion, Peripheral oedema
Signs of sepsis: Fever, Tachycardia/bounding pulse, Tachypnoea, Warm peripheries, Local signs of sepsis
Cardiac: Pericardial rub
Respiratory: Pulmonary oedema/effusion
Abdominal: Ascites/masses/bladder
CNS: Drowsiness/confusion
Skin: Rashes
What blood tests can be done to test renal function?
Biochemistry: Creatinine, eGFR, Na/K, Bicarbonate, Ca/Phos/PTH, CRP, CK
Haematology: Hb
Immunology: ANA, ANCA, anti-GBM, complement (C3, C4), electrophoresis (IgA/G/M)
What urine tests can be performed to look at renal function?
Urine dipstix: protein, blood ACR/PCR: quantify protein 24h creatinine clearance Urine output MSU: check for infection Urine creatinine/electrolytes/calcium
What radiological studies can be done to test for renal issues?
Renal tract USS CT renal angiogram CT KUB Plain AXR KUB IVP Renogram CXR
What is the initial management of acute kidney injury?
Keep the patient alive: Hyperkalaemia, Fluid overload, Hypotension, Acidosis, Uraemia
Generic management of AKI: Fluids, Stop nephrotoxins
Diagnose cause of AKI (& treat)
What ECG changes might be present with Hyperkalaemia?
Peaked “tented” T waves Prolonged P-R interval Prolonged QRS duration Loss of P waves VF/asystole
What management can be performed for Hyperkalaemia?
Stabilise myocardium: Ca Gluconate
Shift K+ into cells: Insulin+Dextrose, Salbutamol, NaBic if acidotic
Treat ARF, treat cause
Dialysis
What would be subsequent management strategies for acute kidney injury?
Close observation: BP, pulse, Daily weight, Fluid balance assessment, resp function (Sats, RR, O2 requirement)
Daily U&E
Review medications (nephrotoxins/dose adjustment)
Manage underlying cause
When might ICU need to be informed and involved with acute kidney injury management?
Hypotensive secondary to sepsis
Hypotensive and fluid overloaded
Hypotension is not responding to fluid resuscitation
If >1 organ failure
When might a renal specialist registrar need to be involved in the care of a patient with acute kidney injury?
Pre-renal AKI not rapidly resolving with supportive therapy
Doubt about cause of AKI
Blood/protein in urine or other reason to suspect intrinsic AKI
Life-threatening complications (HyperK, fluid overload)
What are mortality rates with acute kidney injury?
10% in uncomplicated AKI
>50% in AKI with multi-organ failure
What were the NCEPOD summary recommendations on acute kidney injury management?
Emergency admissions should have risk assessment for AKI and electrolytes checked on admission and appropriately thereafter
Predictable avoidable AKI should not occur
Acute admission receive senior review (consultant within 12 hours)
Sufficient critical care and renal beds to allow rapid step up care
Undergraduate medical training should include recognition of acutely ill patient and prevention, diagnosis and management of AKI
Postgraduate training in all specialties should include training in detection, prevention and management of AKI
What are the stages of chronic kidney disease?
Stage 1: kidney damage with normal GFR, over 90
Stage 2: kidney damage with mild decrease GFR, 60-89
Stage 3: moderate decrease in GFR, 30-59
Stage 4: severe decrease in GFR, 15-29
Stage 5: kidney failure, GFR <15, for dialysis
What can be complications of chronic kidney disease?
Cardiovascular disease Hypertension Anaemia Bone-mineral metabolism Poor nutritional and functional status Progression of CKD AKI
What tests can be used to measure chronic kidney disease?
Tests for renal excretory function: Creatinine, Cystatin C, eGFR
Urinalysis: haematuria
Urine protein: 24h urine collection, Urine albumin:creatinine ratio (sensitive at low levels, recommended in diabetes), Urine protein:creatinine ratio
Tests for complications: Hb, K+, sBic, cCa, PTH
Diagnostic blood tests: ANCA, electrophoresis, Glc
Radiological tests: USS, CT, DMSA
What is the relationship between creatinine levels and kidney function?
Creatinine levels remain fairly constant until a large loss of function so may not be an accurate measurement of normal function. Good measure for relatively end stages CKD
What is significant progression of CKD?
Sustained decline in GFR of 25% or more and a change in category in within 12 months
Or sustained decline in GFR of 15ml/min/1.73m2 per year
What risk factors are associated with progression of CKD?
Hypertension Diabetes mellitus Albuminuria Cardiovascular disease Smoking Ethnicity NSAIDS
What are the consequences of late presentation of CKD?
Higher mortality, morbidity, hospital stay, cost
Due to poorer clinical state at presentation, lack of vascular access
No possibility of pre-emptive transplantation
What is established renal failure?
Stage of chronic kidney disease where renal replacement therapy is required to safely sustain life
What is the treatment of established renal failure?
Dialysis: Haemodialysis (hospital, satellite, home), Peritoneal dialysis (CAPD, APD)
Transplantation: Deceased-donor transplant, Living-donor transplant (including pre-emptive)
Conservative care
What are Considerations when discussing RRT modality?
Physical & social factors: Eyesight & manual dexterity, Mobility and functional status, Family and social support, Work
Medical factors: Abdominal surgery, Vascular disease, Hypotension/left ventricular dysfunction
Geographical factors: Distance from haemodialysis unit, Space/cleanliness of house
What are pros and cons of renal replacement therapy?
Pro-RRT: Increased survival, Decreased uraemic symptoms
Con-RRT: 3x4h/week (+travel), Dialysis access procedures & complications,mdoes not cure other comorbidities
Name some anatomical relations of the kidneys
Suprarenal glands Liver Transverse mesocolon Jejunum Stomach Spleen Pancreas 2nd part duodenum Costodiaphragmatic recess Quadratus lumborum Psoas major 12th rib
