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
2
Q
Limitations of creatinine clearance
A
Exceeds true GFR x 10-20% due to tubular secretion
Secretion increases with drop in GFR
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
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
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
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
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
8
Q
What is the role of ADH
A
- Maintain plasma osmolality - via V2 receptor, mutation in receptor → nephrogenic diabetes insipidus
- Volume regulator - when fall in arterial blood volume → fall in systemic BP → increase ADH - water retention via V2, increased vascular resistance via V1 receptors
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
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
11
Q
Causes of SIADH
A
- Ectopic secretion of ADH - small cell lung carcinoma (most common tumour)
- Any CNS disorder
- Drugs - carbamazepine, SSRI, chemo, immunosupressants, ciprofloxacin, amiodarone, ecstasy
- Any recent surgery (mediated via pain afferents)
- Pulmonary disease
- Hormone deficient - hypopituitarism and low TSH
- Idiopathic - normally due to occult tumour or GCA
12
Q
Causes of euvolaemic hypotonic hyponatraemia
A
- Excessive water ingestion normally secondary to psychiatric illness → kidneys able to excrete up to 10L/day
- Low dietary solute intake but high fluid intake - alcoholics, tea and toast diet
- Advanced renal failure - increased solute excretion but impaired water excretion despite normal levels of ADH
- Thiazide diuretics - often patients euvolaemic, reduction in diluting ability of kidney
13
Q
Causes of hypovolaemic, hypotonic hyponatraemia
A
- Renal fluid losses secondary to excessive diuretics - high urine sodium and chloride
- GI losses such as diarrhoea or 2rd spacing → low urine sodium
- GI losses due to vomiting → high urine sodium in severe metabolic alkalosis - sodium excretion with loss of urinary bicarbonate, low urine chloride
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
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
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
-
Stimuli for secretion:
-
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
- Lactic acidosis
- Ketoacidosis
- Rhabdomyolysis
- Advanced renal failure
- 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
Broad classification of renal tubular acidosis based on potassium status
**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
Notes on Distal (Type 1) RTA
* **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
Notes on Type 2 Renal tubular acidosis (proximal)
* 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
Notes on Type 4 RTA/Hypoaldosteronism
* 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
Notes on proximal convulted tubule
* 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
Notes on the Distal Convoluted tubule
* 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
Notes on SGLT2 co-transporters
* 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
