REPRO/NEPHRO BLOCK: Week 3 - Kidneys

What proportion of body weight is extracellular or intracellular fluid?

Which factors affect fluid movement between compartments across endothelium barriers? These are found between intravascular and extravascular components (i.e. extracellular fluid).

What factors affect fluid movement between compartments across cell membranes? These are found between extracellular and intracellular compartments.

What happens to the body fluid compartments when only water is given to the patient?

What happens to the body fluid compartments when the patient is given only sodium?

What happens to the body fluid compartments when the patient is given sodium AND water, i.e. isotonic saline infusion?

What are the 3 features of the glomerular filtration barrier?

What is the normal GFR?

Which part of the nephron contains tight junctions between cells?

How much of the Na/Cl is absorbed in the PCT?

What is the most accurate description of the process of tubular secretion?

Describe ADH action. 1. ADH binds to [blank_start]V2 receptors[blank_end] ([blank_start]G protein coupled[blank_end] receptors) on the basolateral side of collecting duct cells 2. This causes a [blank_start]conformational change[blank_end] in the receptor, leading to the alpha subunit activating adenine cyclase 3. This stimulates [blank_start]cAMP[blank_end] production 4. This stimulates [blank_start]PKA[blank_end] production 5. This causes [blank_start]increased[blank_end] expression of [blank_start]aquaporins[blank_end] in the cell membrane, allowing more [blank_start]water reabsorption[blank_end]

What are the 3 effects of ADH?

What membrane transporters are found in the collecting duct? 1. [blank_start]ENaC[blank_end] (function: [blank_start]reabsorption[blank_end] of Na+) 2. [blank_start]K+ channel[blank_end] (function: [blank_start]excretion[blank_end] of K+) 3. [blank_start]H+ channel[blank_end] (function: [blank_start]excretion[blank_end] of H+)

What is the function of the macula densa?

Change in kidney function in reduced tubular flow due to decreased blood flow: 1. Sensed by the [blank_start]macula densa[blank_end] 2. [blank_start]Granular (mesangial) cells[blank_end] produce [blank_start]renin[blank_end] 3. Renin stimulates the renin-angiotensin system: results in the production [blank_start]angiotensin II[blank_end] 4. [blank_start]Angiotensin II[blank_end] causes [blank_start]vasoconstriction[blank_end] of the efferent arteriole ---This [blank_start]increases[blank_end] pressure in the glomerulus ---This [blank_start]increases[blank_end] hyperfiltration and thus tubular flow 5. [blank_start]Angiotensin II[blank_end] also stimulates [blank_start]aldosterone[blank_end] secretion ---This increases sodium retention via [blank_start]ENaC[blank_end]

Change in kidney function in increased tubular flow due to increased blood flow: 1. Sensed by the [blank_start]macula densa[blank_end] 2. Macula densa produces [blank_start]adenosine[blank_end] 3. [blank_start]Adenosine[blank_end] causes [blank_start]afferent arteriolar constriction[blank_end] 4. This [blank_start]decreases[blank_end] blood flow to the kidney

Describe renal excretion of drugs via glomerular filtration protein binding. 1. Some drugs can enter the tubules via [blank_start]glomerular filtration[blank_end], e.g. if they are: ---[blank_start]Small molecules[blank_end] ---[blank_start]Not bound[blank_end] to plasma proteins 2. These drugs can then be [blank_start]excreted[blank_end] in the urine ---NOTE: this cannot happen to large drugs (e.g. [blank_start]heparin[blank_end]) or those bound to plasma proteins

Describe renal excretion of drugs via tubular secretion independent of protein binding. 1. [blank_start]Active transport[blank_end] of drugs into the tubule from the [blank_start]capillary[blank_end] 2. There are 2 routes of tubular secretion: ---[blank_start]Basic carriers[blank_end] ------Carry [blank_start]basic drugs[blank_end] (i.e. alkaline), e.g. --------->[blank_start]Amiloride[blank_end] --------->[blank_start]Dopamine[blank_end] --------->[blank_start]Histamine[blank_end] ---[blank_start]Acidic carriers[blank_end] ------Carry [blank_start]acidic drugs[blank_end], e.g. --------->[blank_start]Frusemide[blank_end] (loop diuretic) --------->[blank_start]Penicillin[blank_end] --------->[blank_start]Indomethacin[blank_end] (NSAID) 3. Drugs are excreted in the urine very rapidly after secretion into the tubules 4. To prolong therapeutic effect: ---Agents can be prescribed to [blank_start]block[blank_end] tubular reabsorption

Describe reabsorption dependent manipulability of drugs in the kidney. 1. After entering the tubules (either through [blank_start]reabsorption[blank_end] or [blank_start]secretion[blank_end]), drugs are either: ---[blank_start]Excreted[blank_end] in the urine ---[blank_start]Reabsorbed[blank_end] into the blood 2. Drugs are [blank_start]passively reabsorbed[blank_end] into the bloodstream together with [blank_start]water[blank_end]

Which of these drugs are excreted by the kidneys without first being metabolised, i.e. are largely unchanged?

How can you measure creatinine clearance, used as a measure of kidney function? 1. [blank_start]Formal clearance[blank_end] (via 24 hour urine collection) 2. [blank_start]Isotope renogram[blank_end] 3. [blank_start]isohexol clearance[blank_end] 4. [blank_start]Inulin clearance[blank_end] 5. [blank_start]Formulae[blank_end] (which take into account factors which change creatinine clearance, e.g. age, sex)

How do the kidneys excrete drugs? 1. [blank_start]Glomerular filtration protein binding[blank_end] 2. [blank_start]Tubular secretion[blank_end] independent of protein binding 3. [blank_start]Reabsorption dependent manipulability[blank_end]

What are the effects of impaired kidney function on drug metabolism/clearance? 1. Altered pharmacokinetics: ---[blank_start]Decreased drug elimination[blank_end] ---[blank_start]Decreased drug absorption[blank_end] ---[blank_start]Altered drug metabolism[blank_end] ---[blank_start]Altered drug distribution[blank_end] 2. Altered drug effects ---[blank_start]Increased sensitivity to drugs[blank_end] ---[blank_start]Decreased sensitivity to drugs[blank_end] 3. Worsening of existing renal impairment ---[blank_start]Impairment of renal function[blank_end] ---[blank_start]Increased fluid retention[blank_end] ---[blank_start]Uraemia and renal failure[blank_end] 4. [blank_start]Enhancement of adverse effects[blank_end] 5. [blank_start]Decreased clearance[blank_end]

What are the 5 main effects of impaired renal function on drug metabolism? 1. [blank_start]Altered pharmacokinetics[blank_end] 2. [blank_start]Altered drug effects[blank_end] 3. [blank_start]Worsening of existing renal impairment[blank_end] 4. [blank_start]Enhancement of adverse effects[blank_end] 5. [blank_start]Decreased clearance[blank_end]

Which factors affect the effects of renal impairment on drug metabolism? 1. [blank_start]Extent of renal decompensation[blank_end] 2. [blank_start]Extent of renal elimination of drugs[blank_end] 3. [blank_start]Therapeutic index of drugs[blank_end]

What are the different types of nephrotoxicity? 1. [blank_start]Acute tubular necrosis[blank_end]/[blank_start]direct nephrotoxicity[blank_end] 2. [blank_start]Drug-related glomerulonephritis[blank_end] 3. [blank_start]Interstitial nephritis[blank_end] 4. [blank_start]Nephrogenic diabetes insipidus[blank_end]

How do ACE inhibitors cause nephrotoxicity? 1. Normally, if the sensed volume is reduced, [blank_start]angiotensin II[blank_end] causes [blank_start]vasoconstriction[blank_end] of the [blank_start]efferent arteriole[blank_end] to maintain glomerular filtration pressure and GFR 2. [blank_start]ACE inhibits[blank_end] prevent the action of [blank_start]angiotensin II[blank_end] 3. Therefore there is no vasoconstriction of the efferent arteriole 4. Therefore, glomerular filtration pressure and GFR [blank_start]decreases[blank_end] ---This causes kidney function impairment, i.e. nephrotoxicity

How do NSAIDs cause nephrotoxicity? 1. Normally, in reduced sensed volume, [blank_start]prostaglandins[blank_end] cause [blank_start]vasodilation[blank_end] of [blank_start]afferent arterioles[blank_end] in the nephron (while angiotensin II causes vasoconstriction of efferent arterioles) to maintain GFR 2. NSAIDs [blank_start]inhibit[blank_end] the action of prostaglandins 3. Therefore, there is [blank_start]no vasodilation[blank_end] of afferent arterioles 4. Therefore, glomerular filtration pressure and GFR [blank_start]decreases[blank_end] ---This causes kidney function impairment, i.e. nephrotoxicity

How does gentamicin cause nephrotoxicity? 1. [blank_start]High peaks[blank_end] are needed for antibacterial activity, but this creates [blank_start]prolonged trough levels[blank_end] 2. [blank_start]Prolonged trough levels[blank_end] cause [blank_start]toxic side effects[blank_end], which affect the [blank_start]PCT[blank_end] 3. Development of kidney failure depends on: ---[blank_start]Underlying kidney disease[blank_end] ---[blank_start]Hydration[blank_end] ---[blank_start]Age[blank_end] ---[blank_start]Cumulative dose[blank_end]

In what condition would you always AVOID giving ACE inhibitors and NSAIDs?

What are hydrostatic forces, and where are they greatest?

What are the 3 factors which affect the extracellular fluid volume/composition? 1. [blank_start]Salt intake[blank_end] 2. [blank_start]Water intake[blank_end] 3. [blank_start]Salt/water losses[blank_end]

What are the features of the tubular epithelium in the proximal convoluted tubule? 1. [blank_start]Tight junctions[blank_end] 2. [blank_start]Aquaporin I[blank_end] 3. [blank_start]Na+ cotransporters[blank_end]

What are the features of the tubular epithelium in the thin descending loop of Henle? 1. [blank_start]Loose junctions[blank_end] 2. [blank_start]Aquaporin I[blank_end]

What are the features of the tubular epithelium in the thick ascending limb of the loop of Henle? 1. [blank_start]Impermeable to water[blank_end] 2. [blank_start]Na+/K+/2Cl- channel[blank_end] ([blank_start]NKCC channel[blank_end])

What are the features of the tubular epithelium in the collecting duct? 1. [blank_start]Aquaporin II, III, IV[blank_end] 2. [blank_start]ENaC[blank_end] ([blank_start]epithelial Na channel[blank_end])

Which part of the nephron is completely impermeable to water?

What stimulates ADH secretion?

Which structure is responsible for sensing decreased volume, and consequently stimulating ADH production?

Which structure is responsible for sensing increased serum osmolality, and consequently stimulating ADH production?

Describe the counter-current exchange multiplier. 1. [blank_start]Na+[blank_end] and [blank_start]other electrolytes[blank_end] are transported out of the [blank_start]thick ascending loop of Henle[blank_end] (via [blank_start]Na+/K+/2Cl- channel[blank_end]) a. The [blank_start]ascending loop[blank_end] is impermeable to water, so this stays in the lumen b. This creates a [blank_start]very high[blank_end] concentration of electrolytes in the [blank_start]interstitium[blank_end] and [blank_start]capillaries[blank_end] 2. The [blank_start]vasa recta[blank_end] around the loop of Henle flow in the [blank_start]opposite[blank_end] direction to the nephron, so the high concentration of electrolytes is moved to surround the [blank_start]thin descending loop of Henle[blank_end] 3. The [blank_start]large concentration gradient[blank_end] creates a [blank_start]large osmotic gradient[blank_end] around the [blank_start]thin descending loop of Henle[blank_end] a. This allows for the reabsorption of large amounts of [blank_start]water[blank_end] from the descending loop 4. This also creates a [blank_start]very concentrated[blank_end] filtrate in the descending loop, which then moves on to the ascending loop – this increases reabsorption of electrolytes along the concentration gradient in the ascending loop

Describe the renin-angiotensin-aldosterone system (RAAS). 1. [blank_start]Renin[blank_end] is secreted by the [blank_start]juxtaglomerular cells[blank_end] in the kidney, stimulated by: a. Increased [blank_start]sympathetic innervation[blank_end] b. Decreased [blank_start]afferent arteriole pressure[blank_end] c. [blank_start]Hyperkalaemia[blank_end] d. [blank_start]Decreased Na+/Cl-[blank_end] levels in the DCT (sensed by the [blank_start]macula densa[blank_end]) 2. [blank_start]Renin[blank_end] stimulates conversion of [blank_start]angiotensinogen[blank_end] into [blank_start]angiotensin I[blank_end] 3. [blank_start]Angiotensin I[blank_end] is converted to [blank_start]angiotensin II[blank_end] by [blank_start]angiotensin converting enzyme (ACE)[blank_end] 4. Effects of [blank_start]angiotensin II[blank_end]: a. [blank_start]Vasoconstriction[blank_end] (via AII/AT1 receptors) b. Stimulates [blank_start]sodium reabsorption[blank_end] in the nephron c. Stimulates [blank_start]aldosterone[blank_end] secretion from the adrenal cortex d. Stimulates [blank_start]ADH[blank_end] secretion from the posterior pituitary gland e. Stimulates [blank_start]thirst centres[blank_end] in the brain f. Enhances [blank_start]sympathetic[blank_end] adrenergic innervation g. Stimulates cardiac and vascular hypertrophy

How does aldosterone increase sodium and fluid retention? 1. [blank_start]Increased expression of ENaC[blank_end] (via preformed vesicles) 2. [blank_start]Increased stability of ENaC[blank_end] 3. [blank_start]Increased activity of Na+/K+ ATPase[blank_end]

What is the juxtaglomerular apparatus made of? 1. [blank_start]Macula densa[blank_end] (in the DCT) 2. [blank_start]Juxtaglomerular cells[blank_end] (around the afferent arteriole) 3. [blank_start]Mesangial cells[blank_end] (in the glomerulus)