Kidney Function 3

What is constant plasma osmolality maintained by?

A balance of urine formation and thirst

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What is a concentrated urine?

Osmolality greater than plasma (>300 mosmol/L). Obliged to eliminate 600 mosmol of waste products each day. Maximum urinary concentration is 1400 mosmol/L. Obligatory water loss is 0.428 L of urine/day (varies, increased in tissue catabolism/fasting)

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What is oliguria?

Output below the level

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What is dilute urine? (1)

Osmolality less than plasma (<300 mosmol/L). As low as 50 mosmol/L. Normal urine output is 1-2 L/day. Polyuria (excessive urine output). Maximum urine output ~ 23 L/day (but capacity of bladder is 500 mL)

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What is dilute urine? (2)

Dehydration urine colour chart (hydrated - clear/straw colour, low bubbles, low odour, signs of water intoxication, water diabetes/osmotic diuresis)

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What is osmolar clearance? (1)

Clearance of all osmotically active particles, calculated in similar way to clearance of individual substances. C = UV/P (urine osmolality x flow rate / plasma osmolality)

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What is osmolar clearance? (2)

Can be viewed as volume of plasma cleared of osmotically active particles per unit time or fictive urine urine flow that would have results in urine which is isomolar to plasma. Fasting osmolar clearance ~ 2-3 mL/min

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Describe features of free water clearance (1)

Used to assess renal function. C = V - (UV/P), urine flow rate minus osmolar clearance. CH2O (reflects ability of kidneys to excrete dilute/concentrated urine)

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Describe features of free water clearance (2)

CH2O > 0 (indicated hypo-osmotic urine/dilute urine). CH2O = 0 (iso-osmotic urine with respect to plasma). CH2O < 0 (hyper-osmotic urine/concentration urine). Possible CH2O range -1.3 to 14.5 mL/min (maximum anti-diuresis, complete absence of ADH)

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Describe features of free water clearance (3)

Kidney able to separate Na/H2O reabsorption. Able to maintain plasma osmolality 285-295 mosmol/L. Maintains plasma volume within functional limits ~ 3.5 L

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Outline the process of anti-diuresis

Low water intake (dehydration). Increased plasma osmolality. Detected by osmoreceptors in hypothalamus. Posterior pituitary gland secretes ADH. Increased ADH levels to kidney. More water reabsorption. Less water excreted in urine

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Outline the process of diuresis

High water intake (over-hydration). Decreased plasma osmolality. Detected by osmoreceptors in hypothalamus. Posterior pituitary gland doesn't secrete ADH. Decreased ADH levels to kidney. Less water reabsorption. More water excreted in urine

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Where are the osmoreceptors located? (1)

In the organum vasculosum lamina terminalis (OVLT), median preoptic nucleus (MPN), subformical organ (SFO). Signal to magnocellular neurosecretory cels in paraventricular and supraoptic nuclei in hypothalamus

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Where are the osmoreceptors located? (2)

Precursor molecule for ADH (166 amino acids long, passed along axon to pituitary gland, cleaved, at terminal ending, ADH/9 amino acid peptide). Cells produce/release ADH into blood/carotid artery through posterior pituitary (via axon).

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Describe the control of ADH release (1)

Very effective due to short half life of 10-20 mins. ADH release is rapid. ADH actions are rapid (2nd messenger effect). Plasma ADH conc and plasma osmolality. Above threshold of 280 mosmol/kg, linear relationship

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Describe the control of ADH release (2)

ADH conc variable even within normal range of 285-295 mosm/kg. Person doesn't become thirsty until plasma osmolality is above 295 mosm/kg. Below this, changes in ADH release affects water concentration in blood

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What are the other factors that affect ADH secretion? (1)

BP and blood volume. 5% decrease in blood volume and 10% decrease in BP cause neuronal release of ADH from posterior pituitary. Osmolality (1% change required to cause effect on ADH secretion)

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What are the other factors that affect ADH secretion? (2)

ADH also known as vasopressin (ADH can also cause constriction of systemic arterioles, allows BP/blood volume to be increased, vasoconstriction to return blood volume/BP to normal). Ang II increases ADH and natriuretic peptides decrease ADH)

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What are the main controllers of ADH?

Osmoreceptors

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ADH levels are affected by what other factors?

Alcohol (inhibits ADH). Nicotine (stimulates ADH). Nausea (stimulates ADH). Pain (stimulates ADH). Stress (stimulates ADH)

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Describe the action of ADH on the collecting duct

Acts on V2 receptor on basolateral membrane on collecting duct. 2nd messenger effect. Causes AQP2 insertion on luminal membrane. Water reabsorption

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What is diabetes insipidus?

Water diabetes (to pass through, having no flavour). Generate excessive urine (urination >2 L/day). Losing water, become thirsty (polydipsia). Nocturia (empty bladder at night). Normal ion concentrations in urine

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What are the two types of diabetes insipidus?

Neurogenic - no ADH secreted, congenital or due to head injury (trauma/brain tumour). Nephrogenic - inherited (mutated V2 receptor or AQP2) or acquired (infection or side effect of drug e.g. lithium)

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What is osmotic diuresis? (1)

Increased urination due to small molecules (glycerol, mannitol and excess glucose). Typical of untreated diabetes mellitus. High Na/K excreted. Polyuria and polydipsia

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What is osmotic diuresis? (2)

Increased glucose concentration. Increase GF of glucose. Increased osmolality in filtrate. Decreased water reabsorption from proximal tubule. Later portions of nephron cannot compensate. Dilute urine, glucose in urine

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Describe features of how potassium is handled by the body (1)

Major intracellular cation in body. 5 mM EC fluid. 150 mM IC. Gradient main determinant of resting membrane potential. Ingest 40-120 mmoles K+/day. Need to balance ingested K+

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Describe features of how potassium is handled by the body (2)

Renal excretion, secreted into colon and expelled from body via faeces (GI loses), redistributed into cells (cellular shifts). 98% of total body K+ is located inside cells. Majority of cells are located in skeletal muscle

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Describe features of renal excretion of potassium (1)

Filtration, reabsorption, secretion. Kidney filters 800 mmoles/day (95% reabsorbed at proximal tubule). Passive K+ reabsorption. K+ moved between cells (follows movement of Na/H2O) at proximal tubule

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Describe features of renal excretion of potassium (2)

No luminal membrane transporters involved in moving K+ into cell. K+ channel and K-Cl co-transporters on basolateral membranes

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Describe features of K+ transport pathways in thick ascending limb

Na-2Cl-K+ co-transporter. 30% reabsorbed at thick ascending limb. K+ moves through K+ channels and K-Cl co-transporters (NKCC2) on basolateral membrane. + charge in filtrate (repelled by K+). 5% reabsorbed in distal tubule via K-H exchanger

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Describe features of K+ transport pathways in collecting duct (intercalated and principal cells) (1)

K+ reabsorbed by intercalated cells (in exchange for H+). Outweighed by K+ secretion by principal cells. Exit routes - K+ channels (renal outer medullary K+ channel, ROMK), Ca 2+ activated big-conductance K+ channel, BK), K-Cl co-transporter, luminal

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Describe features of K+ transport pathways in collecting duct (intercalated and principal cells) (2)

Use of Na-K ATPase pump (once secreted, it can be excreted in urine). K+ excreted in urine (is the K+ that has been secreted)

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Which factors affect K+ secretion by principal cells (collecting duct) (1)

Factors affecting Na+ entry through epithelial Na+ channels (ENaC, movement of K+ depends on electrochemical gradient, if Na leaves, form - charged filtrate, supports K+ down gradient into filtrate)

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Which factors affect K+ secretion by principal cells (collecting duct) (2)

Aldosterone stimulates K+ channels (by stimulating activity of Na channels, change electrochemical gradient for K+ and increase activity of ROMK, also increase activity of Na-K ATPase pump, increase K+ secretion/excretion)

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Which factors affect K+ secretion by principal cells (collecting duct) (3)

High tubular flow rates favour K+ secretion. Washing any K+ secreted away, maintain low K+ conc in filtrate, supports movement of K+ via K+ channel. Increase K+ secretion via K+ channels on luminal membrane

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Which factors affect K+ secretion by principal cells (collecting duct) (4)

Acidosis inhibits K+ secretion/excretion (associated with higher H+ in plasma/filtrate, affects electrochemical gradient to drive K+ via K+ channel)

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Which factors affect K+ secretion by principal cells (collecting duct) (5)

Alkalosis (lower H+ in plasma/filtrate, increase electrochemical gradient for K+, movement into filtrate), increase K+ secretion/excretion. Normal plasma K+ 3.5-5.0 mM

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Describe features of hypokalaemia (1)

Plasma [K+] < 3.5 mM. Mild (3.0-3.5 mM). Moderate (2.5-3.0 mM). Severe (K+ <2.5). Caused by - increased external losses (kidney e.g. diuretics, osmotic diuresis, transporter mutations e.g. ENaC, hyperaldosteronism, alkalosis

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Describe features of hypokalaemia (2)

(GI tract e.g. vomiting, diarrhoea, skin e.g. burns, intense sweating), redistribution into cells (metabolic alkalosis, insulin excess) and inadequate K+ intake (starvation and prolonged fasting)

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Describe features of hypokalaemia (3)

Increased external loses in urine due to higher tubular flow rates which increase K+ secretion/excretion e.g. loop diuretics, thiazide diuretics, transporter mutations, osmotic diuresis

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How do loop diuretics, thiazide diuretics and transporter mutations increase tubular flow rates?

Loop diuretics (thick ascending limb), thiazide diuretics (distal tubule), transporter mutations inhibit Na+ (and K+ for loop diuretics) which inhibits water reabsorption. Osmotic diuresis is due to excess solutes in filtrate. Wash K+ in filtrate

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What is Liddle's syndrome?

Transporter mutations

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How does hyperaldosteronism stimulate K+ secretion and excretion?

Aldosterone increases activity of Na+ channel, K+ channel and Na-ATPase pump (principal cells of collecting duct

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How does alkalosis cause hypokalaemia? (1)

Normal plasma pH (7.35-7.45, 35-45 nM free H+). Alkalosis (pH >7.45, hypokalaemia). Acidosis (pH<7.35, hyperkalaemia). Kidney - increased external loss. K+ secretion in principal cells increased by alkalosis, changes in electrochemical gradient

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How does alkalosis cause hypokalaemia? (2)

Secretion of K+ through K+ channels. Redistribution into cells - H+ ions bound to intracellular proteins (buffer) will leave cells to return plasma pH to normal and K+ take place inside cells. (Skeletal muscle has the largest volume of IC fluid)

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Outline the redistribution into cells (what is the other cause of K+ redistribution?)

Insulin excess shifts potassium into cells. Insulin (maintains glucose concentrations and K+ concentrations). Binds to insulin receptor, increase in activity of Na-K ATPase pump, K+ movement into cells

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What are the signs and symptoms of hypokalaemia? (1)

Vm determined by K+ gradient. RMP more negative (hyperpolarised), nerves have to be depolarised more to reach threshold for AP firing. Repolarisation is slower so cells closer to threshold for longer

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What are the signs and symptoms of hypokalaemia? (2)

Cardiac (dysrhythmias, conduction defections, increase likelihood of dysrhythmias due to digitalis). Skeletal muscle (weakness, respiratory/paralysis, fasciculations and tetany), GI (ileus, nausea, vomiting, abdominal distention). Renal (polyuria)

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What are the signs and symptoms of hypokalaemia? (3)

Symptoms may not appear in mild hypokalaemia. Muscle pain may be experienced by moderate hypokalaemia. Severe hypokalaemia (fatal)

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How is hypokalaemia treated?

Replace K+. Eat food which are rich in potassium (e.g. bananas, spinach). KCl administration (oral or IV). Alkalosis correction. Use of K+ sparing diuretics e.g. spironolactone, amiloride

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What is hyperkalaemia? (1)

Plasma [K+] > 5.5 mM. Caused by decreased external losses (renal failure/persistent, hyperaldosteronism, action of drugs). Redistribution out of cells (acidosis - exacerbated by lack of insulin in diabetic ketoacidosis)

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What is hyperkalaemia? (2)

(tissue destruction/cell lysis e.g. rhabdomyolysis)

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What is hyperkalaemia? (3)

Mild (5.5-6.5 mM). Moderate (K+ > 6.5-7.5). Severe (K+ >7.5 mM)

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What are the signs and symptoms of hyperkalaemia? (1)

RMP determined by gradient. Shift in RMP closer to threshold for AP firing (depolarises excitable cells)

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What are the signs and symptoms of hyperkalaemia? (2)

Cardiac (dysrhythmias conduction disturbances). Skeletal muscle (weakness, parethesias, paralysis, hyperreflexia, cramping). GI (nausea, vomiting, diarrhoea). Renal

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How is hyperkalaemia treatment? (1)

Short term (calcium IV to antagonist effect of K+ on heart muscle, stabilise cardiac membrane). Intermediate term (insulin administered to shift K+ into cells, plus glucose to prevent hypoglycaemia, shifting K+ into cells)

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How is hyperkalaemia treatment? (2)

Long term (increase K+ excretion with diuretics e.g. loop diuretics and thiazide diuretics, or treat renal failure, remove K+ from the body)

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Kidney Function 3

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