REN Flashcards
What is a fluid?
A substance that deforms under a shear stress. Importantly, one in which water or fat/lipid is the solvent.
What are the key compartments?
Intracellular water
Interstitial water- filling the space between cells, amongst the extracellular matrix
Fat
Plasma
Transcellular fluid- separated from extracellular fluid by a membrane e.g. CSF, peritoneal fluid, aqueous humour
How do you calculate the volume of distribution?
Inject a substance known to distribute into a given compartment and calculate the Vd. The volume of fluid required to contain the total amount of drug in the body at the same concentration as is present in the plasma.
Vd= Q/Cp where Q is amount of drug and Cp is the plasma concentration of the drug.
How is plasma volume estimated?
Labelled proteins are injected intravascularly; Evan’s Blue
How is extracellular fluid volume estimated?
36Cl-, thiosulphate, thiocyanate, inulin.
What is plasma?
Fluid component of the blood, usually represents about 55% of blood by volume. Rest of the volume is occupied by cells.
What is haematocrit?
Measure of the proportion of blood occupied by cells. (45%)
What are the constituents of the body fluids?
E=Extracellular, I=Intracellular Na+ E>I K+ E<i>I Cl- E>I HCO3- E>I Glc E>I Osmolarity ~285mOsmkg-1</i>
What is Ca2+ in the blood like?
Half bound to albumin so any change in albumin will change the total Ca concentration without changing the free Ca conc.
Free Ca is biologically active and more interesting, body regulates free Ca not total Ca.
What is an osmole?
Measure of the number of molecules that a compound dissociates into when dissolved in solution.
What is the difference between osmolality and osmolarity?
Osmolality is the number of osmoses per unit mass of the solvent. (Osmkg-1)
Osmolarity is the number of osmoles per unit volume of the solution. (Osml-1)
What is osmotic pressure?
The force per unit area required to oppose the movement of species along its conc grad. It is the amount of pressure required to oppose osmosis.
Define isosmotic
Two solutions have the same osmolality
Define isotonic
Applying the solution to cells will not cause a net movement of fluid
What is oncotic pressure?
The osmotic pressure due to proteins in the capillaries
What is a normal renal plasma flow rate?
600mlmin-1
Which forces drive filtration in the glomerulus?
1) Hydrostatic- higher hydrostatic pressure (50mmHg) in the capillaries drives fluid out, much higher than that in most capillaries.
2) Osmotic/oncotic pressure- higher osmotic pressure in the capillaries due to plasma proteins impedes the flow.
What are the main ways to locally increase the pressure in the glomerular capillary?
Dilate the afferent arteriole
Constrict the efferent arteriole
What are the main ways to locally increase the pressure in the glomerular capillary?
Dilate the afferent arteriole
Constrict the efferent arteriole
What is the equation for osmotic pressure?
Osmotic pressure = nCRT (nC=osmolality, 0.28osmkg-1 and R= ideal gas constant 0.082Latmmol-1K-1 and T= temperature, 310K)
What are the glomerular barriers to diffusion?
1) Endothelial cells of the glomerular capillaries- with fenestrations between them
2) Glomerular basement membrane- fixed negatively charged proteins
3) Epithelial cells of Bowman’s capsule
What are podocytes?
Epithelial cells of Bowman’s capsule, they have small pedicels that project and interdigitate with their neighbours to form another barrier to the movement of fluid.
Which molecules are filtered in the kidney?
Most molecules less than 10kDa in size, Na+, K+, Mg2+, Ca2+, Cl-, HCO3-, glucose and urea.
Larger molecules may be found, if + or if glomerular damage causes leaking
What is a normal GFR?
120mlmin-1 or 180lday-1
What is the use of hydrostatic P in the Bowman’s space?
Helps to drive movement of fluid through the rest of the kidney.
What is the filtration fraction?
Proportion of plasma flow filtered by the glomerulus. GFR/RPF
How can GFR be measured?
Measured using substances that are freely filtered but neither secreted or absorbed in the tubes.
Substance can be injected intravenously or produced by the body at a steady rate (creatinine).
How is creatinine in urine measured? How is the rate of production worked out?
Amount: Ccru x V
Rate: (Ccru x V)/t
How do you work out GFR?
GFR x Ccr,p
(Ccru x V)/t = GFR x Ccr,p
GFR = (Ccru x V’)/(Ccr,p)
What is an empirical GFR estimate?
Taking a blood sample. Relies on info that Cr production is constant with age and correlated with age sex and mass. At equilibrium, rate of production = rate of loss through kidney so GFR varies inversely with Ccrp.
eGFR = k/Ccr,p
What happens to GFR with age?
Progressively lose nephrons and GFR falls causing Cr to rise.
What is the significance of proteinuria?
Glomerular dysfunction. Key feature of a key set of renal failures which when sufficiently severe, constitute nephrotic syndrome. Glomerulonephritis.
What is the transport in the proximal convoluted tubule?
Selective distribution of ion channels, exchangers and pumps on apical and basolateral membranes are key to directional ion movement. Movement is trans and paracellularly. Movement of Na+ creates an osmotic P gradient for the movement of water transcellularly and paracellularly. This segment of the tubule is water permeable implying that the filtrate is nr isotonic with the interstitial space which in the cortex means that it is effectively isotonic with plasma. By the end of the tubule about 70% of water is reabsorbed.
What are the different forms of transport in the PCT?
Uses the movement of Na+ down its electrochemical gradient to drive the movement of other substances like glc and amino acids.
Uses the Na+/K+ ATPase to move Na+ out of the cell on the basolateral membrane.
How does water move in the PCT?
Both paracellular route and the transcellular route through AQP1. Paracellularly by net outward hydrostatic and osmotic forces.
What is the fate of each of the following in the PCT?
a) Absorbed? b) Conc at end of tubule
1) Inulin
2) Urea
3) Chloride
4) Na+ and K+
5) HCO3-
6) Amino acids
7) Glucose
1) No / Higher
2) Weakly / Higher
3) Weakly / Higher
4) Yes / Same
5) Yes / Lower
6) Strongly / Much lower
7) Strongly / Much lower
How is glucose absorbed in the PCT?
90% transported by low affinity/high capacity SGLT2, rest by high affinity low capacity SGLT1. Basolateral transport by GLUT2 or GLUT1.
Maximal tubular load of glucose, about 380mgmin-1
How are amino acids absorbed in the PCT?
Plasma amino acid concentration is 2.5-3.5mM. Transport is Tm limited. Many different transporters, mostly cotransporters using the Na+ gradient.
How is HCO3- absorbed in the PCT?
Reaction with excess H+ entering through a Na+/H+ exchanger. Rate at which eq is achieved is increased by carbonic anhydrase. Basolateral transport uses Na+/3HCO3- transporter.
What is acetazolamide?
Blocks carbonic anhydrase so is a weak diuretic and is used in glaucoma and mountain sickness prophylaxis. It can cause a metabolic acidosis, makes urine alkaline.
How is Cl- absorbed in the PCT?
Both active and passive transport. Active- through antiproton for other anions (HCO3- or HCOO-).
Because HCO3- is also absorbed in the PCT, with its charge balanced by Na+ absorption, less Cl- is moved than Na+. Water is reabsorbed with these which means that [Cl-] increases along the tubule so as this increases the paracellular movement of Cl- is driven by the conc grad.
What happens to albumin in the PCT?
Albumin that has been filtered binds to the plasma membrane of the tubule and is endocytose then catabolised into its amino acids for subsequent recycling in the body.
What is secreted in the PCT?
Penicillin, PAH, furosemide, negative charge often comes from carboxylates of sultanates. Ions compete for excretion. Basolateral membranes- organic anion transporters, luminal membrane- multi drug resistance- associated protein, MRP.
What is the key function for the thick ascending limb of the loop of Henle?
To create a hyperosmolar interstitial space in the medulla to drive water loss from the descending limb and cortical collecting duct. It pumps out Na and Cl and is water impermeable.
What are the functions of the thin descending limb?
Permeable to water which leaves the filtrate due to osmotic force.
What does the thick ascending limb do?
Sustains an osmotic gradient of about 200mOsmkg-1.
Uses the Na+/K+/2Cl- cotransporter to move ions out of the filtrate. Common abbreviation NKCC2. K+ recycling through the apical membrane is necessary to ensure transporter can maintain its role in transporting large quantities of Na+ and Cl-.
What is furosemide?
Acts in the ascending limb of the loop of Henle- loop diuretic.
Blocks Na+/K+/2Cl- co transporter.
Allows up to 20% of filter Na+ to be excreted causing enormous natriuresis and diuresis. It is used in cardiac failure and renal failure.
Side effects- K+ loss and subsequent hypokalaemia leading to cardiac dysrhythmias particularly when administered with digoxin. Other side effects include hypovolaemia, mild metabolic alkalosis and loss of Mg2+ and Ca2+.
What is the countercurrent mechanism for osmolality?
- Process (same text as syllabus notes, but points listed separately)
a. The active reabsorption of Na+ and Cl- in the ascending thick limb of juxtamedullary nephrons combined with the thick limb impermeability to water results in an increased osmolality in the renal medulla.
b. The increased medullary interstitial osmolality draws water from the descending thin limb, progressively concentrating the fluid remaining in the tubular lumen.
c. As this fluid passes around the hairpin turn and flows into the ascending limb, it loses NaCl into the interstitium by passive diffusion in the ascending thin limb and by active transport in the ascending thick limb.
d. As a result, interstitial fluid throughout the whole medulla becomes hyperosmotic and the fluid leaving the ascending thick limb and entering the distal tubule is hypoosmotic. - Because this process occurs as the fluid is flowing along the loop of Henle and exchange takes place between the interstitium and fluid streams moving in opposite directions (descending and ascending) and because osmolality increases progressively with depth in the medulla, the mechanism is termed countercurrent multiplication.
- The interstitial osmolality is further increased by the accumulation of urea (explained later).
What are thiazides?
Act in distal tubule Block Na+/Cl- co transporters Moderately effective diuretics Used as an antihypertensive As a diuretic in conjunction with furosemide
What is spironolactone?
Acts in the collecting tubules and ducts, blocks the effect of aldosterone. Moderately effective diuretics. Used in heart failure (K+ sparing diuretic)
What are the side effects of spironolactone?
Gynaecomastia, menstrual disorders, testicular atrophy hyperkalaemia.
What is urea countercurrent multiplication?
Urea concentration rises in the DCT and cortical collecting duct because water is reabsorbed and they are impermeable to urea. In the medullary collecting duct, urea diffuses out of the tubule as ADH increases permeability and expression of UT-A1. Urea adds to high osmotic P in the medulla and aids water reabsorption.
What is urine concentration and flow regulated by?
ADH
What is ADH?
Synthesised in the hypothalamus, released from hypothalamic neurones in the posterior pituitary, acts in the distal tubule and collecting duct to increase water permeability by increasing AQP2 on the apical membrane.
How does ADH act?
V2 receptor GPCR, leads from Gs to AC to cAMP via ATP. From cAMP there is a long term and a short term pathway.
Long term- Nucleus +ve transcription to AQP2 synthesis to vesicles containing AQP2 to apical membrane.
Short term- PKA increases insertion.
What is the osmolality in the nephron when there is no ADH?
PCT- 285 LOH- 600 down to 90 DCT- 90 Collecting duct- 60 In the absence of ADH, water cannot cross this segment so osmolality doesn't equilibrate with the cortex at 285. Ions are pumped out and end up with diluted urine.
What is the osmolality in the nephron with maximum ADH?
PCT- 285 LOH- 1400 down to 90 DCT- 285 Collecting duct- 1400 Osmolality can now equilibrate with the cortex so water can leave and exchange across a segment. Water leaves to equilibrate with the medulla so high osmolality urine.
