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Renal > Renal Physiology > Flashcards

Renal Physiology Flashcards

1
Q

Points on creatinine

A

Serum creatinine - from metabolism of creatine in skeletal muscle and dietary meat intake, varies depending on age, sex, body size, freely filtered across glomeruli and not reabsorbed - also secreted by proximal tubules

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2
Q

Limitations of creatinine clearance

A

Exceeds true GFR x 10-20% due to tubular secretion
Secretion increases with drop in GFR

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3
Q

% components body water, ECF, ICF

A
  • Body water - 60%, lower in high BMI due to fat and loss of muscle mass
  • ECF - 33%
  • Main cation - sodium
  • Main anion - chloride and bicarbonate
  • ICF - 66%
  • Main cation - potassium
  • Main anion - oganic phosphates
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4
Q

Measurement of plasma osmolality and how it is regulated

A
  • Plasma osmolality in mmol = (2xNa) + glucose + urea
  • Small contributions from glucose and urea except in cases of uncontrolled DM and reduced renal function
  • Regulation: via osmoregulators/ADH in hypothalamus -> regulate water intake/excretion, increase thirst and release of ADH, extremely sensitive and plasma osmolality tightly controlled
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5
Q

Place of action of diuretics

A
  • Acetozolamode → proximal convoluted tubule
  • Loop diuretics → thick ascending loop of henle
  • Thiazides → distal tubule
  • Potassium sparing diuretics → collecting tubule principal cells → inhibit reabsorption of sodium and excretion of potassium
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6
Q

Response to increase in plasma osmolality

A

Detected by osmoreceptors in the hypothalamus

  • Stimulates increase water intake by thirst
  • Stimulates neurohypophysis of posterior pituitary to secrete ADH
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7
Q

MOA ADH

A
  • Binds to V2 receptors in nephron (thick ascending limb -> collecting ducts) - Release of AQP2
  • Chronic stimulation ADH → increased phosphorylation AQP2 → binds to tubular membranes allowing free entry of water into cell
  • Short term stimulation → release of preformed vesicles of AQP2
  • Water then leaves cell via basolateral membrane via AQP3 and AQP4
  • Once stimulation ceased - AQP2 returns to cells
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8
Q

What is the role of ADH

A
  1. Maintain plasma osmolality - via V2 receptor, mutation in receptor → nephrogenic diabetes insipidus
  2. Volume regulator - when fall in arterial blood volume → fall in systemic BP → increase ADH - water retention via V2, increased vascular resistance via V1 receptors
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9
Q

Notes on Tolvaptan

A
  • Blocks V2 receptors in distal nephron and collecting duct
  • Prevents binding of vasopressin → reduces expression of aquaporins
  • Promotes water excretion → polyuria and potential dehydration
  • Important to maintain adequate hydration to prevent activation of V1 receptors
  • PCKD → reduces cyst formation
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10
Q

Features of SIADH

A
  • Euvolaemic hypotonic hyponatraemia → low serum sodium, low plasma osmolality, high urine osmolality (> 100), normally also high urine sodium and normal serum potassium and pH
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11
Q

Causes of SIADH

A
  1. Ectopic secretion of ADH - small cell lung carcinoma (most common tumour)
  2. Any CNS disorder
  3. Drugs - carbamazepine, SSRI, chemo, immunosupressants, ciprofloxacin, amiodarone, ecstasy
  4. Any recent surgery (mediated via pain afferents)
  5. Pulmonary disease
  6. Hormone deficient - hypopituitarism and low TSH
  7. Idiopathic - normally due to occult tumour or GCA
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12
Q

Causes of euvolaemic hypotonic hyponatraemia

A
  1. Excessive water ingestion normally secondary to psychiatric illness → kidneys able to excrete up to 10L/day
  2. Low dietary solute intake but high fluid intake - alcoholics, tea and toast diet
  3. Advanced renal failure - increased solute excretion but impaired water excretion despite normal levels of ADH
  4. Thiazide diuretics - often patients euvolaemic, reduction in diluting ability of kidney
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13
Q

Causes of hypovolaemic, hypotonic hyponatraemia

A
  1. Renal fluid losses secondary to excessive diuretics - high urine sodium and chloride
  2. GI losses such as diarrhoea or 2rd spacing → low urine sodium
  3. GI losses due to vomiting → high urine sodium in severe metabolic alkalosis - sodium excretion with loss of urinary bicarbonate, low urine chloride
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14
Q

Causes of hypervolaemic hypotonic hyponatraemia

A
  • Increase in ECF colume
  • Lack of cardiac output in heart failure
  • Reduced tissue perfusion → activation of ADH secretion → water retention → oedema
  • Arterial vasodilatation → cirrhosis
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15
Q

Causes of hypertonic hyponatraemia

A
  • Hyperglycaemia → increase in serum osmolality → water drawn from cells → expands ECF and lowers serum Na concentration
  • IVIG → hyperteonic solution
  • Sorbitol or mannitol irrigation in urological or gynaecological procedures → expansion of ECF
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16
Q

Notes on sodium reabsorption in kidneys

A
  • 67% of sodium reabsoprbed in proximal convoluted tubule via osmotic gradient of water (as water gets reabsorbed sodium goes with it)
  • 25% Na absorbed in thick ascending limb of loop of henle via K/Na transporter - ascending limb impearmeable to water
  • 5% Na reabsorbed in distal convoluted tubule via the Na/Cl transporter
  • 3% sodium reabsorbed in the collecting ducts - stimulation of sodium pumps by aldosterone
  • <1% of sodium in the filtrate is excreted in the urine
17
Q

Notes on Barter’s Syndrome

A
  • Barter = baby
  • AR inheritance
  • Childhood onset, more severe than Gitelman’s, can cause perinatal death
    • Mimicks therapy with loop diuretics
    • Impairment of transporters in loop of Henle
    • High levels of prostaglandin production → stimulates renin
18
Q

Notes on Gitelman’s syndrome

A
  • Gitelman = grown-ups
  • Less severe than Barter’s, mimics therapy with thiazides
  • Defect in distal tubule

See attached slide for differences between Barter’s and Gitelman’s

19
Q

Notes on internal potassium homeostasis and agents that increase uptake of potassium into muscle and tissue

A
  • Body content of potassium
    • 98% intracellular
    • 2% extracellular
  • Increase uptake into muscle and other tissues
    • Via Na-K-ATPase pump in cell membranes
    • Insulin
    • Aldosterone
    • Catecholamines, growth hormones
    • Increase in pH in ECF - alkalosis
20
Q

Notes on renal potassium handling

A
  • 62% potassium reabsorbed in proximal tubule
  • 20% absorbed in the thick ascending limb of loop of Henle
    • Can also be reabsorbed in the distal tubule in the case of low potassium diets
  • Plasma potassium level regulated by secretion of potassium in the collecting ducts
    • Stimuli for secretion:
      • Dietary K
      • Aldosterone
      • Acid-base
      • Flow rate
      • Luminal anions
  • Hyperkalaemia often leads to metabolic acidosis and vice versa
    • High plasma K levels increase the entry of K into cells which is buffered by hydrogen ion moving out -> acidosis of plasma and intracellular alkalosis
    • In a metabolic acidosis - increased hydrogen ion load -> hydrogen ion into cells - shifts potassium out of cells (and sodium) -> actual reading may be normal or reduced if there are external sources of K loss such as GI or urinary losses
21
Q

Role of kidneys in acid-base balance

A
  • Reclaim filtered bicarbonate
    • Reabsorption occurs in proximal tubules and collecting tubules
    • 85% reclaimed in proximal tubule via the sodium/hydrogen exchange pump on the tubular membrane
    • Remaining reclaimed in collecting tubule following secretion of hydrogen ions via proton pumps H-ATPase > H-K ATPase
    • No bicarbonate in urine in normal subjects
  • Excrete daily acid load from food intake
    • From sulfer-containing amino acids
    • Normally occurs in the collecting tubules - as above secretion H+ via H-K ATPase pump and the H-ATPase pump
    • Hydrogen ions bind to ammonia and phosphate in urine which allows the pH gradient to remain within a range (minimum of 4.5 - 5)
    • Kidneys make ammonia upon stimulation by intracellular acidosis
22
Q

Types of metabolic acidosis

A
  • High anion gap metabolic acidosis
    • Increased acid generation
  • Normal anion gap metabolic acidosis (hyperchloremic)
    • Loss of bicrabonate
    • Diminished renal acid excretion
  • Anion gap = (Na + K) - (Cl + HCO3)
    • In normal anion gap acidosis - drop in HCO3 compensated by increase in Cl
23
Q

Causes of high anion gap metabolic acidosis

A
  1. Lactic acidosis
  2. Ketoacidosis
  3. Rhabdomyolysis
  4. Advanced renal failure
  5. Ingestion → methanol, aspirin, paracetamol overdose, inhalant abuse
24
Q

Causes of normal anion gap/hyperchloraemic metabolic acidosis

A

Loss of bicarbonate

  • Severe diarrhoea
  • Using ileum to replace a bladder → Na and HCO3 losses
  • Renal failure → due to accumulation of anions such as sulphate and phosphate
  • Proximal Type 2 RTA

Impaired renal acid excretion

  • Moderate renal impairment
  • Distal (Type 1) RTA and type 4 RTA
25
Q

Broad classification of renal tubular acidosis based on potassium status

A

Hypokalaemia

  • Classic distal Type 1 → defects in distal hydrogen ion excretion
  • Proximal type 2 → reduced capacity to reclaim filtered bicarbonate

Hyperkalaemia

  • Type 4 → Hypoaldosteronism

Type 3 = combination type 1 and type 2 → very rare

26
Q

Notes on Distal (Type 1) RTA

A
  • Urine pH >5.5 in the setting of a normal anion gap metabolic acidosis
  • Hypercalciuria, hypocitraturia, nephrolithiasis
    • Metabolic acidosis release calcium phosphate from bones to buffer the retained acid
    • Reduction of tubular absorption of calcium and phosphate ? Increase urinary levels
    • High urine pH precipitates calcium phosphate
    • High urine pH also reduces citrate excretion (normal citrate forms a soluble complex with calcium)
  • Hypercalciuria can also be a causative disease
  • Hypokalaemia in Distal RTA (Type 1)
    • Sodium is reabsorbed in exchange for a cation -> impaired hydrogen ion secretion -> increase K secretion
    • Metabolic acidosis in PCT - reduce Na reabsorption - stimulates aldosterone - K wasting
    • Hypokalaemia reversed with alkali therapy
      • Increase sodium bicarbonate to distal nephron increases urine pH -> more hydrogen ion is secreted before saturating gradient occurs
      • Sodium load expands ECF volume 0 reduces drive for sodium reabsorption and reduces aldosterone secretion
  • Treatment
    • Alkali therapy with bicarbonate tablets
      • Bind retained hydrogen ions
    • Return sodium bicarbonate levels to normal
27
Q

Notes on Type 2 Renal tubular acidosis (proximal)

A
  • Sodium hydrogen ion pump in the proximal tubule is defective - reduced reabsorption of bicarbonate
  • Features
    • Urine pH <5.5
    • Serum bicarbonate 12-20
    • Upon rapid correction of serum bicarbonate to normal
      • Re-absorptive ability of kidneys become saturated
      • Excessive secretion of bicarbonate
      • Rapid rise in urine pH >7.5
  • Causes
    • Monoclonal gammopathies, Fanconi’s syndrome, drug,
    • Can occur with other defects such as impaired reabsorption of phosphate, glucose, uric acid and/or amino acids
  • Generally no issues with renal stones
  • Treatment:
    • More difficult to treat than distal
    • Ingested bicarbonate -> bicarbonate diuresis
    • Much higher doses required to overcome losses
    • Bicarbonate diuresis - stimulates potassium secretion - hypokalaemia
28
Q

Notes on Type 4 RTA/Hypoaldosteronism

A
  • High serum K
  • Mild normal anion gap metabolic acidosis
  • Causes
    • Hyporeninemic hypoaldoteronism
      • NSAIDs or calcineurin use, chronic interstitial nephritis or DM nephropathy, acute GN
    • Treatment with Angiotensin II inhibitors, K sparing diuretics
    • Heparin - toxic effect on adrenal zona glomerulosa cells
    • Primary adrenal insufficiency/Addison’sNo
  • Treatment
    • Treat underlying disorder if possible
    • Fludrocortisone - mineralocorticoid replacement therapy
      • Caution is required as can lead to fluid retention
29
Q

Notes on proximal convulted tubule

A
  • Largest surface area
  • 60-65% sodium reabsorbed
  • Major site of bicarbonate absorption
  • Glucose predominantly absorbed here
  • Amino acid reabsorbed
  • All absorbed through sodium transporters and Na/K ATPase (baselateral membrane)
  • Probenecid - site of action - interferes with organic anion transporter on basolateral membrane - increased plasma level of penicillin
    • Interferes with URA on apical membrane - unable to reabsorb urinary uric acid → can be used for prophylaxis of gout
  • Phosphate
    • Reabsorbed proximal tubule via sodium/phosphate cotransporter
    • Internalisation of the pump in response to FGF23 = Phosphaturia
30
Q

Notes on the Distal Convoluted tubule

A
  • Proximal
    • 5% NaCl reabsorbed
    • Thiazides work here
    • Rate of absorption of sodium proportional to amount of sodium in lumen
    • Thiazides compete for chloride site
    • Thiazides cause increased calcium reabsorption due to increased positive charge in filtrate
    • 2-5% magneisum absorpbed here - TRPM6/M7 channel
      • Load dependent, negative potential
      • Channel inhibited by tacrolimus
      • Role of epidermal growth factor receptors - mutations - isolated hypomagnesaemia, antagonists - tyrosine kinase inhibitors such as gefitinib
31
Q

Notes on SGLT2 co-transporters

A
  • SGLT 2 co-transporter - located on apical membrane of proximal tubules
    • Na extruded from cell via Na/K ATPase pump on basolateral membrane
    • Allows glucose to be reabsorbed down concentration gradient
    • 80-90% of glucose reabsorbed in early segments of proximal tubules
    • Remaining 10% reabsorbed through SGLT1 in proximal tubules

Renal (7 decks)

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