Kidneys Flashcards
What cells make up the PCT?
Simple cuboidal epithelial cells with brush border on apical side to increase surface area
What features aid reabsorption in the PCT?
Brush border (increases surface area) Large number of channels in apical and basolateral membranes (large surface area for transport of ions) Large amounts of mitochondria (for energy)
What is paracellular transport?
Solutes transported via intercellular spaces between cells
What is transcellular transport?
Transportation of solutes through a cell
What are the functions of the kidneys?
Regulation of body fluid (volume + composition)
Excretion of metabolic waste + toxins
Endocrine functions
What are the key processes involved in urine formation?
Filtration
Reabsorption
Secretion
What makes up a uriniferous tubule?
Nephron + collecting duct
[Nb. many nephrons drain into the same collecting duct]
What makes up a nephron?
Renal corpuscle
PCT
Loop of Henle
DCT
What makes up a Renal corpuscle?
Glomerulus + Bowman’s Capsule
What 2 capillary beds does the blood in the kidneys have to pass through and what are their functions?
- Glomerular capillaries (under high pressure for filtration)
- Peritubular capillaries/ Vasa Recta (under low pressure for reabsorption and secretion)
What is the benefit of having arterioles at either end of the glomerular capillary bed?
Allows high pressure for filtration
What is the function of mesangial cells in the renal corpuscle?
Provide support between glomerular capillary loops
What makes up the filtration barrier of the Glomerulus?
- Fenestrated glomerular capillary endothelium
- Negatively charged basement membrane
- Epithelial cells - interdigitated podocytes with filitration slits
[limiting movement to small, positively charged molecules]
What is the function of the filtration barrier of the Glomerulus?
Limits passage of substance from the blood based on their size, charge and shape
What happens in the PCT?
Majority of water, Na+, Cl-, amino acids + glucose reabsorption (65% of water and Na+)
Some secretion of drugs and waste molecules
Which parts of the Loop of Henle are permeable to water?
Thin descending limb
[Thin + thick ascending limbs both impermeable to water]
Where in the Loop of Henle does active reabsorption of solutes take place?
Thick ascending limb [generates hyperosmolar interstitium in medulla]
What cells make up the lining of each part of the uriniferous tubule?
PCT = simple cuboidal with microvilli Thin descending = simple squamous Thin ascending = simple squamous Thick ascending = simple cuboidal DCT = simple cuboidal Collecting Duct = simple columnar
What happens in the DCT?
Active reabsorption of solutes (esp. Na+)
Secretion of K+ and H+
Variable water permeability (dependent on location and ADH presence)
What are the components of the Juxtaglomerular Apparatus (JGA)?
- Macula Densa
- Extraglomerular mesangial cells (Lacis cells)
- Granular cells in afferent arteriole
What is the role of the collecting duct?
Regulates degree of urine concentration - under the control of ADH (which determines water permeability of the duct)
What is the distribution of fluid throughout the body?
Extracellular:
Plasma = 3L
Interstitial fluid = 11L
Intercellular fluid: 28L
How is fluid lost from the body?
Kidneys Lungs Faeces Sweat Skin
What are capillary membranes permeable to?
Water and electrolytes
[not plasma proteins meaning that interstitial fluid and plasma composition is similar except for the proteins which remain in the plasma]
What are cell membranes permeable to?
Water but not most electrolytes
How does the composition of intra- and extracellular fluid differ?
ECF:
Main cation = Na+ and main anion = Cl-
ICF:
Main cation = K+ and main anion = PO4 (phosphate)
What are the main osmotically active electrolytes?
ECF = sodium ICF = potassium
What is the rate of urinary excretion determined by?
Filtration rate + Secretion rate - Reabsorption rate
What is the Glomerular Filtration Rate (GFR) and what determines this?
Volume of filtrate formed by all the nephrons in both kidneys per unit of time
Determined by Glomerular Capillary Filtration Coefficient (Kf) and Net Filtration Pressure (NFP)
So GFR = Kf x NFP
What does the filtration coefficient (Kf) reflect?
Surface area and permeability (hydraulic conductivity)
How is net filtration pressure determined?
Sum of the hydrostatic pressure (Glomerulus + Bowman’s Capsule)
Sum of the colloid osmotic pressure (Glomerulus + Bowman’s Capsule)
What is the typical net filtration pressure?
10mmHg
What is the key regulator of GFR?
Changes in glomerular hydrostatic pressure (Pg) - this depends on:
Arterial (blood) pressure
Afferent arteriole resistance
Efferent arteriole resistance
What changes in arteriole resistance increases GFR?
Afferent arteriole dilation &/or efferent arteriole constriction
What changes in arteriole resistance reduce GFR?
Afferent arteriole constriction &/or efferent arteriole dilation
What vasoconstrictors have an effect on GFR (via their effects on glomerular hydrostatic pressure/ NFP)?
Angiotensin II (constricts EA, increasing Pg) Prostaglandins + Atrial Natriuretic Peptide (dilate AA, increasing Pg) NA, Adenosine and Endothelin (constrict AA, reducing Pg)
What pressure changes favour reabsorption in the peritubular capillaries?
Lower hydrostatic pressure
Higher colloid osmotic pressure
What are the 2 mechanisms of autoregulation of GFR?
Myogenic response (inherent ability of smooth muscle in afferent arterioles to respond to changes in vessel circumference by contracting or relaxing) Tubuloglomerular feedback
How does myogenic autoregulation respond to an increase in BP?
- Stretch of afferent arteriole smooth muscle cells in response to increased renal blood flow/ GFR (in response to increased BP)
- Calcium channels open
- Reflex contraction of afferent arteriole smooth muscle (vasoconstriction)
- Increased resistance to blood flow
- Prevents changes in renal blood flow and GFR
How does tubuloglomerular feedback autoregulate GFR in response to increased BP?
- Macula Densa cells (in DCT) sense high NaCl (increased BP = increased GFR = increased delivery of NaCl to DCT)
- Release of paracrine factors (e.g. Adenosine)
- Constriction of AA smooth muscle (vasoconstriction)
- Increased resistance to blood flow restores renal blood flow + GFR
How does tubuloglomerular feedback autoregulate GFR in response to decreased BP?
- Macula Densa cells (in DCT) sense low NaCl (decreased BP = decreased Pg = decreased GFR = decreased delivery of NaCl to DCT)
- Release of Renin increases levels of Angiotensin II
- Angiotensin II increased efferent arteriole resistance
[Nb. Macula Densa cells sensing low NaCl also directly acts on smooth muscle of AA to vasodilate, decreasing resistance]
What investigations can be used to assess renal function?
Urine analysis
Bloods (waste products, electrolyte abnormalities, underlying causes)
Imaging (structural or functional abnormalities)
Biopsy (e.g. malignancy)
What urine abnormalities indicate renal damage?
Proteinuria + Albuminuria (indicate damage to filtration barrier)
Haematuria (can originate anywhere in the urinary system)
What blood tests can be done to indicate renal function?
GFR/eGFR (most accurate)
Serum Creatinine/ Urea
Electrolytes/ pH
Haemoglobin
How can GFR be measured?
Renal clearance (volume of plasma from which a substance is completely cleared by the kidneys per unit time) Based on the fact that the amount of substance cleared from plasma per minute [substrate concentration x volume of plasma cleared] is equal to the amount of substance appearing in urine per minute [substance concentration x volume of urine cleared]
Clearance (ml/min) = V (urine production, ml/min) x U (substance concentration in urine, mg/ml) / P (substance concentration in plasma, mg/ml)
This equation quantifies the kidneys ability to eliminate substances from plasma
What substances can be used to assess clearance?
Must be freely filtered across the glomerulus (with this being the only route of excretion, so not reabsorbed or secreted), non-toxic and easily measured
Inulin (a plant polysaccharide) is an accurate measure of GFR but it technically difficult to do
How (and why) is Creatinine used to measure clearance?
Creatinine formed from breakdown of Creatine (skeletal muscle component) at a steady rate - is freely filtered at glomerulus and not reabsorbed (although small amount of secretion tends to overestimate GFR)
Requires 24 hour urine collection (so issues with compliance, time etc.)
What is urea?
Nitrogen-containing metabolic waste product from the metabolism of proteins
Serum urea levels tend to rise in kidney disease as GFR falls
What factors increase urea production?
High protein diet
Increased catabolism (trauma, infection, surgery, cancer)
GI bleed
Drugs (corticosteroids, tetracyclines)
What factors reduce urea elimination?
Renal disease causing decreased GFR
Poor renal blood flow (e.g. dehydration or low BP)
How are serum urea and creatinine used to assess renal function?
Both increase as renal function declines
If urea is raised, should always be compared to creatinine:
1. if both have increased in parallel then fall in GFR is likely cause
2. if urea is disproportionately higher then other factors must be considered (e.g. dehydration, high protein diet, GI bleed or catabolic state)
What factors affect serum creatinine levels?
Muscle mass (affected by age, sex, amputation, malnutrition, muscle wasting, ethnicity) Diet
[Nb. serum creatinine not useful in detecting early decline of renal function as you can lose approx. 50% of GFR before levels are out of normal ranges]
What factors are used to estimate GFR?
Serum creatinine, age, sex, ethnicity
CKD-EPI equation
What are the limitations of using eGFR as an indicator of renal function?
No measurement of body size included meaning that factors affecting muscle mass are missed (e.g. patient with amputation would have lower serum creatinine than expected for age, sex, ethnicity and would therefore have an incorrectly high eGFR)
Also limited use in children, AKI and drug dose calculations for highly toxic drugs
Still more accurate than Serum Creatinine alone!
How is glucose reabsorbed in the PCT?
Against concentration gradient across luminal membrane via Sodium-Glucose Co-transporters (esp. SGLT2)
Crosses basal membrane by facilitated diffusion via Glucose transporters (GLUT)
What is the glucose transport maximum?
Finite number of SGLT transporters in proximal tubule cells so increase in glucose reaches a transport maximum where reabsorption cannot go any faster causing loss of glucose in urine
How is hydrogen secreted in the PCT?
Secondary active transport via Na+/H+ exchanger
[Important for bicarbonate reabsorption in acid-base balance]
How are solutes reabsorbed in the thick ascending limb?
Primarily via Na+K+2Cl co-transporters
Also via paracellular diffusion of cations (Na+, K+, Mg2+, Ca2+) down concentration gradient
How is sodium reabsorbed in the early DCT?
Sodium-chloride co-transporters on luminal membrane
Crosses basal membrane via Na+/K+ exchange
What are the 2 main cell types found in the late DCT and cortical collecting duct?
Principal cells (Na+ reabsorption, K+ secretion) Intercalated cells (H+ secretion, K+ reabsorption)
How is sodium reabsorbed in the principal cells of the DCT/ Cortical collecting duct?
Crosses luminal membrane via epithelial Na+ channels (ENaC)
Transported out of cell via Na+/K+ ATPase
[Nb. number of channels and ATPase pumps increase in presence of ALDOSTERONE]
How and where does aldosterone regulate tubular processing?
Where: collecting tubule and duct
How: increased reabsorption of NaCl and H2O, increased secretion of K+ by binding to intracellular mineralocorticoid receptors which then bind to the cell’s nucleus and increase production of proteins (e.g. ENaC and Na+/K+ ATPase)
How and where does angiotensin II regulate tubular processing?
Where: PCT, thick ascending loop of Henle, DCT, collecting tubule
How: increased reabsorption of NaCl and H2O and increased secretion of H+ by increasing activity of sodium transporters in tubular cells
How and where does ADH regulate tubular processing?
Where: late DCT, collecting tubule and duct
How: increased reabsorption of H2O
How and where does Atrial Natriuretic Peptide (ANP) regulate tubular processing?
Where: DCT, collecting tubule and duct
How: decreased reabsorption of NaCl, released by atrial muscle fibres in response to increased stretch of atria (due to excessive blood volume)
How and where does parathyroid hormone (PTH) regulate tubular processing?
Where: PCT, thick ascending loop of Henle, DCT
How: decreased reabsorption of phosphate, increased reabsorption of calcium
How can receptors detect changes in electrolyte levels?
Directly (e.g. K+ concentration in ECF has direct effect on release of Aldosterone)
Indirectly (e.g. baroreceptors indicate ECF volume (which is a marker of sodium levels)
How can disease states alter our ability to regulate electrolyte levels?
Sometimes precise regulation of one parameter is sacrificed to allow for regulation of another
What is natriuresis?
[Also known as pressure diuresis]
Ability of the kidneys to increase urine output (and increase sodium excretion) in response to an increased BP
How does Renin help to regulate electrolyte levels?
Secreted by granular cells in the JGA in response to fall in extracellular volume/ low sodium
What triggers the release of renin by granular cells in the JGA?
- Low afferent arteriole pressure
- Activation of sympathetic nerves supplying the JGA
- Low NaCl in distal tubule
[Indicators of fall in BP]
Where is the majority of potassium stored in the body?
Intracellular fluid
How does the body regulate potassium levels?
Can manage levels short term by moving potassium between the intra- and extracellular fluid
[Clinical relevance: serum K+ may not be a good indicator of K+ levels due to this]
What factors favour K+ movement into cells (to decrease ECF levels)?
Insulin (used in emergency treatment of hyperkalaemia)
Aldosterone (increases urinary excretion of K+)
Beta-adrenergic stimulation
Alkalosis (due to exchange of intracellular H+ for extracellular K+)
What factors favour K+ movement out of cells (to increase ECF levels?
Insulin deficiency (DM) Aldosterone deficiency (Addison's) Beta-adrenergic blockade Acidosis Cell lysis (releases K+ from ICF due to cell membrane damage) Strenuous exercise Increased ECF osmolarity
Where does the majority of variation in K+ movement take place to regulate K+ excretion?
Potassium secretion in late DCT and cortical collecting tubule
What factors determine the rate of K+ secretion?
Na+/K+ ATPase activity
Concentration gradient between blood, principal cell and lumen
Permeability of luminal membrane to K+
What factors increase potassium secretion?
- Increased plasma K+ concentration (increases gradient from blood to lumen, ATPase activity and aldosterone release)
- Increased Aldosterone release (increases ATPase activity and the permeability of the luminal membrane)
- Increased tubular flow rate (increases permeability of luminal membrane and concentration gradient from cell to lumen)
What factors reduce potassium secretion?
Increased H+ concentration (decreases ATPase activity)
What are the normal ranges of extracellular potassium?
3.5-5.3mmol/L
What is hypokalaemia?
Potassium levels below normal ranges [<3.5mmol/L]
Can be due to reduced intake, excessive potassium loss (e.g. due to diuretics, severe diarrhoea or aldosterone excess) or altered body distribution
What are the signs and symptoms of hypokalaemia?
Often asymptomatic but can have muscle weakness and cardiac arrhythmias
How is hypokalaemia treated?
Manage underlying cause
Supplementation if necessary
What is hyperkalaemia?
Potassium levels above normal ranges [>5.3mmol/L]
Can be due to excessive intake, inadequate losses (e.g. due to kidney disease or aldosterone deficiency) or altered body distribution (e.g. acidosis)
What are the signs and symptoms of hyperkalaemia?
Often asymptomatic but can present with cardiac arrhythmias (ECG will often show characteristic tall T wave)
How is hyperkalaemia treated?
Address underlying cause Restrict intake Calcium gluconate (to stabilise myocardium) Insulin (+glucose) to drive K+ into cells Aid excretion (e.g. fluids, ion-exchange resins and dialysis)
