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What are disorders of sodium balance?

When sodium balance is disturbed, as a result of imbalance between intake and excretion, any tendency for plasma sodium concentration to change is usually corrected by the osmoregulatory mechanism (increased sodium intake increases plasma osmolality, detected by osmoreceptors in supra optic and paraventricular nuclei ---> stimulates ADH release from posterior pituitary --> water reabsorption in distal nephron --> decreases plasma osmolality at expense of a greater ECF)

Because of this, disorders of sodium balance usually present as altered ECF volume rather than altered sodium concentration


Causes of sodium depletion

Inadequate intake
GI sodium loss: vomiting, diarrhoea, external fistulae
Skin sodium loss: excess sweating, burns
Renal sodium loss: diuretics, mineralocorticoid deficiency
Internal sequestration: bowel obstruction, pancreatitis


Clinical features of sodium depletion

Symptoms and signs of hypovolaemia:
- thirst
- dizziness on standing
- weakness
- low JVP
- postural hypotension
- tachycardia
- dry mucous membranes
- confusion
- weight loss

Biochemistry may also show: low plasma sodium, high urea, high urine osmolality, low urine sodium (pre renal AKI)


How should sodium and water depletion be managed?

1) Treat the cause where possible, to stop ongoing salt and water loss

2) Replacement of salt and water deficits, provide ongoing maintenance fluids, by i.v. fusion if depletion is severe

Typical adult requires 2.5-3L of water, 100-140mmol of sodium and 70-100mmol of potassium per day


Causes of sodium excess

If the heart and kidneys are functioning normally, an excessive intake of salt and water is unlikely to lead to clinically obvious features of hypervolaemia

Causes of sodium and water excess include:
- impaired renal function: primary renal disease
- primary hyperaldosteronism: Conn's syndrome
- secondary hyperaldosteronism: CCF, cirrhotic liver disease, nephrotic syndrome

Peripheral oedema is the most common physical sign associated with these conditions, although it is not usually a feature of Conn's syndrome


Management of sodium excess

Management of ECF volume overload involves:
- specific treatment directed at the cause - e.g. ACEi in heart failure, corticosteroids in minimal change nephropathy
- restrict dietary sodium to 50-80mmol/day
- diuretics (loop or thiazide)


The osmoregulatory mechanism means that ECV is altered to normalise plasma osmolality when sodium intake is altered. How is the ECV returned to normal once osmolality has been corrected?

ECV effects reabsorption in the proximal convoluted tubule
Reabsorbed water is added to the venous compartment first, not the arterial one. This ECF volume expansion decreases peritubular capillary protein concentration and plasma oncotic pressure falls. At the same time, capillary hydrostatic pressure increases. These change the Starlings forces causing a decrease in reabsorption and increased delivery of Na to the distal nephron

If water is lost, ECF volume contraction increases reabsorption. Volume contraction increases peritubular capillary oncotic pressure (plasma proteins become concentrated) and capillary hydrostatic pressure falls. These factors increase PCT reabsorption, which returns the ECV back to normal


How do disorders of water balance present?

(in the absence of changes in sodium balance) disturbances of water balance affect plasma sodium concentration, which changes plasma osmolality. The main consequence of changes in plasma osmolality, especially when rapid, is altered cerebral function. This is because, when extracellular osmolality changes abruptly, water flows rapidly across cell membranes, with resultant cell swelling (during hypo-osmolality) or shrinkage (during hyper-osmolality). Cerebral function is very sensitive to such volume changes, particularly during cell swelling, when an increase in intracerebral pressure causes reduced cerebral perfusion.



Plasma Na <135mmol/L
If gradual - asymptomatic
Rapid changes in plasma osmolality and plasma sodium are associated with: anorexia, nausea, vomiting, confusion, lethargy, seizures , coma


Causes of hyponatraemia

Hyponatramia is always associated with a decrease in plasma osmolality, and as a result water shifts INTO the intracellular fluid compartment.

Causes of hyponatraemia are classified based on the volume status of the patient - into hypervolaemic, euvolaemic, and hypovolaemic hyponatraemia


What causes hypovolaemic hyponatraemia?

= net loss of sodium in excess of water (i.e. more sodium is lost than water), hypertonic loss of sodium
Plasma osmolality is decreased and water shifts into the intracellular compartment causing hypovolaemia in the vascular compartment; ECF volume contracts, ICF volume expands
- signs of volume depletion are present

- loop diuretics
- Addison's disease (loss of mineralocorticoids)
- 21 hydroxylase deficiency (loss of mineralocorticoids)


Causes of euvolaemic hyponatraemia

= gain of pure water
Plasma osmolality and serum sodium are decreased, but there is expansion of BOTH the ICF and ECF
Normal skin turgor, because total body Na is normal

- psychogenic polydipsia
- primary polydipsia


What causes hypervolaemic hyponatraemia?

= hypotonic gain of sodium, net gain of water in excess of sodium (i.e. more water is gained than sodium)
Plasma osmolality and serum sodium decrease
Expansion of both compartments
Produces pitting oedema states

- RHF with an increase in venous hydrostatic pressure
- Cirrhosis and nephrotic syndrome with a decrease in plasma oncotic pressure (former from a decrease in albumin and the latter from a loss of albumin in the urine)


What investigations should be performed in hyponatraemia?

Plasma and urine electrolytes and osmolality help classify

Urine Na >20mmol/L
Sodium depletion, renal loss (patient often hypovolaemic)
- diuretics
- Addison's
- diuretic stage of acute renal failure

If patient euvolaemic = SIADH (urine osmolality >500), hypothyroidism

Urine Na <20mmol/L
Sodium depletion, extra renal losses
- diarrhoea, vomiting, sweating
- burns

Water excess (patient often hypovolaemic and oedematous)
- secondary hyperaldosteronism: heart failure, cirrhosis
- redued GFR: renal failure
- IV dextrose, psychogenic polydipsia


Treatment of hypovolaemia

Rx depends on how quickly hyponatraemia develops and the underlying cause.

If hyponatraemia develops rapidly (over hours to days) and there are signs of cerebral oedema (patient is obtunded or convulsing) sodium levels should be rapidly restored to normal by infusion of hypertonic (3%) sodium chloride solution

Rapid correction of hypovolaemia that has developed slowly (i.e. over weeks and months) may lead to central pontine myelinolysis, which may cause permanent structural and functional cerebral changes and is generally fatal. The rate of plasma sodium correction in chronic asymptomatic hyponatraemia should not exceed 10mmol/day

Specific treatments should be directed at the underlying cause


What causes SIADH?

Tumours - esp small cell lung cancer
CNS disorders: stroke, trauma, infection, psychosis
Pulmonary disorders: pneumonia, TB
Drugs: anticonvulsants, psychotropics, antidepressants, cytotoxics, oral hypoglycaemics, opiates



Plasma sodium >148mmol/L, reflects the kidneys inability to concentrate urine in the face of unrestricted water intake

Patients with high sodium generally have reduced cerebral function and cerebral dehydration. This triggers thirst and drinking, and if adequate water is obtained, is self limiting. If adequate water is not obtained, dizziness, confusion, weakness and ultimately coma and death can result.


Causes of hypernatraemia

Hypernatraemia can also be classified based on the volume status of the patient. High sodium increases plasma osmolality creating an osmotic gradient. Water shifts from the ICF (contracts) into the ECF (expands).


What causes hypovolaemic hypernatraemia?

= hypotonic loss of Na+ (net loss of water in excess of Na)
- both POsm and serum Na+ are increased
- both compartments contract
- signs of volume depletion are present

- sweating
- osmotic diuresis
- diarrhoea (osmotic type - laxatives)
- vomiting


Euvolaemic hypernatraemia

= loss of pure water
- both POsm and serum Na+ are increased
- both compartments contract, but ECF contraction is mild because no sodium is lost

- diabetes insipidus
- insensible water loss (e.g. fever, where water evaporates from the warm skin surface)


What causes hypervolaemic hypernatraemia?

= hypertonic gain of Na+ (net gain in sodium in excess of water, i.e. more sodium is gained than water)
- both POsm and plasma Na increase
- ECF compartment expands; ICF contracts

- infusion of sodium bicarbonate or Na+ containing antibiotics
- oral salt administration
- chronic kidney disease (during water restriction)


Management of hypernatraemia

Depends on both the rate and the underlying cause
If condition has developed quickly, correct with appropriate volumes of IV hypotonic fluid
In older patients, it is more likely the disorder has developed slowly and extreme caution should be taken in lowering plasma Na (correct at a rate of 0.5mmol/hr) to avoid the risk of cerebral oedema

Hypovolaemia = isotonic saline if hypotension present then switch to oral replacement or more hypotonic Na+ containing i.v. fluid

Euvolaemic = water replacement

Hypervolaemic = restrict sodium/ remove exogenous cause


Symptoms of hypokalaemia

Asymptomatic if mild (3-3.3 mmol/L). larger reductions cause:
- muscle weakness, tiredeness
- cardiac effects: ventricular ectopics or more serious arrhythmias, potentiation of adverse effects of digoxin
- functional bowel obstruction due to paralytic ileus
- long standing can cause damage to renal tubules (hypokalaemic nephropathy) and interference with the tubular response to ADH (acquired nephrogenic diabetes insipidus) --> polyuria and polydipsia


Causes of hypokalamia

1) Decreased intake - elderly, diet, i.v. therapy

2) Transcellular shift (intracellular)
- Alkalosis: vomiting, loop diuretics, hyperventilation
- Drugs enhancing Na+/K+ ATPase: insulin, salbutamol

3) GI losses - diarrhoea, laxatives, vomiting

4) Renal loss
- loop/ thiazide diuretics (MCC), excessive exchange of Na for K+ in DCT
- osmotic diuresis
- mineralocorticoid excess: primary aldosteronism, 11-hydroxylase deficiency, Cushing's syndrome, secondary aldosteronism (cirrhosis, congestive heart failure, nephrotic syndrome; decreased CO decreases blood flow and activates RAAS)


Hypokalaemia and hypertension

This relates to renal loss of potassium and mineralocorticoid excess:
Primary (Conn's)/ secondary hyperaldosteronism
Cushing's syndrome
Ectopic ACTH
11 beta hydroxylase deficiency


Hypokalamia and normal/low BP

RTA (type 1 and 2)
Post obstructive diuresis
Recovery after acute tubular necrosis
Inherited tubular disorders (Barters syndrome, Gitelman's syndrome)


ECG features of hypokalaemia

Moderate - flattened T wave
Severe - ST depression, U wave


Investigations in hypokalaemia

Plasma electrolytes, bicarbonate, urine potassium and sometimes calcium and magnesium is usually sufficient.

Plasma renin and aldosterone levels identify patients with primary hyperaldosteronism and other mineralocorticoid excess when renin is suppressed. In other causes of hypokalaemia, renin is elevated.

Occasionally the cause of hypokalaemia is obscure (esp if history is incomplete or unreliable and the urine potassium is indeterminate). Many of these cases are associated with metabolic alkalosis, and in this setting measuring the urine chloride concentration can provide helpful guide to diagnosis:
- low urine chloride (<30mmol/L) = vomiting
- high urine chloride (>40mmol/L) = diuretic therapy or tubular disorder


Treatment of hypokalaemia

If problem is redistribution of potassium into cells, treating underlying cause may restore plasma potassium without supplements

Potassium replacement (i.v. or oral)
- rate of administration depends on the severity of hypokalaemia and presence of cardiac or neuromuscular complications
- should not generally exceed 10mmol of potassium/hr
- if higher rates are needed, concentration of K+ infused may be increased to 40mmol/L if peripheral veins are used, but higher concentrations can be infused into a large "central" vein with continuous cardiac monitoring


Symptoms of hyperkalaemia

Typically presents with progressive muscular weakness, but sometimes no symptoms until cardiac arrest occurs (caused by marked slowing of action potential conduction in the presence of K+ levels >7mmol/L)

No universal definition of hyperkalaemia but >5.5mmol/L is generally accepted. Further classified into mild (5.5-5.9mmol/L), moderate (6.0-6.4mmol/L) and severe (6.5mmol/L). If K+ > 6.0mmol/L, do an urgent ECG!


ECG changes in hyperkalaemia

Moderate = peaked T wave
Severe = loss of p waves, widened QRS


Causes of hyperkalaemia

1) Tissue breakdown - pseudohyperkalaemia (e.g. haemolysis of RBCs, thrombocytosis, leukocytosis), rhabdomyolysis

2) Increased intake - infusion of old blood products, K+ containing antibiotics, bananas

3) Transcellular shift - acidosis, drugs inhibiting Na+/K+ ATPase (e.g. propranolol), digitalis toxicity, succinylcholine

4) Decreased renal excretion:
- Renal disease: renal failure, interstitial nephritis (legionnaire's disease, lead poisoning, sickle cell nepropathy, analgesics nephropathy, obstructive uropathy)
- Mineralocorticoid deficiency: Addisons, 21 hydroxylase deficiency, type IV RTA
- Drugs: spironolactone, trimaterene, amiloride


Management of of hyperkalaemia

Treatment depends on severity and the rate of development. In absence of neuromuscular symptoms or ECG changes, reduction of potassium intake and correction of underlying abnormalities may be sufficient.

Acute treatment (K+ >6mmol/L)
1) Stabilise cell membrane potential - i.v. calcium gluconate (10ml of 10%)
2) Shift K+ into cells:
- inhaled beta 2 agonist e.g. salbutamol
- i.v. glucose (50mL of 50% solution) and insulin (5U Actrapid)
- i.v. sodium bicarbonate (if acidosis present)
3) Remove K+ from body
- i.v. furosemide and normal saline (if adequate renal function)
- ion exchange resin (e.g. resonium) orally or rectally
- dialysis


Pathogenesis of respiratory acidosis

Due to alveolar hypoventilation with retention of carbon dioxide
PaCO2 >6.0kPa
Metabolic alkalosis is the compensation
- low serum bicarb suggests an acute respiratory acidosis
- raised serum bicarb (indicating renal compensation) indicates chronic respiratory acidosis


Clinical features of respiratory acidosis

Cerebral oedema (vasodilation of cerebral vessels)
Cyanosis skin/ mucous membranes
Hypoxaemia (reduced PaO2 - retention of CO2 occurs during type II respiratory failure)


Causes of respiratory acidosis

CNS depression - trauma, opiate overdose, barbiturates, brainstem death

Upper airway obstruction - acute epiglottitis, croup, OSA, sleep apnoea, obesity

Chest wall disorders - flail chest, kyphoscoliosis, AS

Muscle disorders - ALS, phrenic nerve injury, GBS, poliomyelitis, MG, hypokalaemia, hypophosphataemia (decreased ATP), botulism

Lungs - COPD, ARDS


Pathogenesis of respiratory alkalosis

Caused by alveolar hyperventilation with elimination of CO2
Metabolic acidosis is the compensation
- low serum bicarb suggests chronic respiratory alkalosis due to renal compensation

Usually a short acid base disturbance, occuring in anxiety states or vigorous exercise. It can be prolonged in pregnancy, PE, chronic liver disease and ingestion of certain drugs that stimulate the brainstem respiratory centre (e.g. salicylates)


Clinical features of respiratory alkalosis

Light headedness and confusion
Characteristic perioral and digital tingling is due to a reduction in ionised calcium caused by increased binding of calcium to albumin in the alkalotic ECF. In severe cases, Trousseau's and Chvostek's sign may be positive, and tetany and seizures can occur


Causes of respiratory alkalosis

CNS overstimulation - anxiety, high altitude, salicylate poisoning, cirrhosis

Chest wall - rib fractures, hyperventilation from pain

Lungs - restrictive diseases: sarcoidosis, asbestosis
- Others: PE, mild bronchial asthma (early phases before they get tired), pneumothorax, mechanical ventilation


What is the pathogenesis of metabolic acidosis?

Respiratory alkalosis is the compensation
Addition of acid to the ECF compartment produces an increased anion gap type of acidosis
Loss of bicarb or inability to synthesise or reclaim bicarb produces a normal AG type of metabolic acidosis
- loss of bicarb is counter balanced by a gain of Cl- ions, therefore normal anion gap metabolic acidosis is also called hyperchloraemic metabolic acidosis


How do you calculate the normal anion gap?

(Na + K) - (Cl + HCO3). If a question supplies the chloride level, then this is often a clue than the anion gap needs calculating. A normal value is between 10-18mmol/L

This value represents anions that are NOT accounted for in the formula (e.g. phsophate, albumin, sulphate) but are normally present in serum. If the anion gap is raised, it means that there are additional anions present that should NOT be there


Pathogenesis of raised anion gap metabolic acidosis

Excess H+ ions from the acid (e.g. lactic acid) are buffered by bicarbonate ions which decreases the serum concentration of bicarb. Loss of bicarb (negative anions) from buffering H+ ions is counterbalanced by anions of the acid (e.g. lactate anions)


Causes of a raised anion gap metabolic acidosis

1) Lactic acidosis
- product of pyruvate metabolism
- MCC raised AG acidosis
- any cause of tissue hypoxia leading to anerobic glycolysis (e.g. shock, CN poisoning, CO poisoning, severe hypoxaemia, severe CHF, anaemia, HONK, DKA - both produce shock by loss of Na+ fluid by osmotic diuresis)
- alcoholism: pyruvate converted in lactic acid from excess of NADH in alcohol metabolism
- liver disease
- renal failure
- drugs: salicylates, methanol, ethylene glycol metabolites

2) Ketoacidosis
3) Renal failure - retention of acids
4) Salicylate poisoning
5) Ethylene glycol poisoning
6) Methyl alcohol poisoning


Features of salicylate poisoning

Aspirin is salicylic acid. It is a mitochondrial toxin that uncouples oxidative phosphorylation, leading to tissue hypoxia and lactic acidosis. In some cases, excess salicylate overstimulates the CNS respiratory centre producing a primary respiratory alkalosis followed by a metabolic acidosis with a raised anion gap.


Clinical features of metabolic acidosis

1) Hyperventilation (Kussmaul breathing)
2) Warm shock - acidosis vasodilates peripheral resistance arterioles
3) Osteoporosis
- bone buffers excess H+ ions causing loss of both organic and mineralised bone


Pathogenesis of metabolic acidosis with normal anion gap

Acidosis is due to loss of H+ ions or an inability to synthesize (regenerate) or reclaim bicarb in the kidneys
Cl- ions increase to counterbalance the reduction in bicarb anions (also called hyperchloraemic normal AG metabolic acidosis)


Causes of metabolic acidosis with normal anion gap

1) Diarrhoea
- MCC in children
- loss of bicarb in stool
- source of bicarb is from the pancreas, which alkalinizes the gastric meal so that pancreatic and small bowel enzymes are functional

2) Cholestyramine - drug binds bicarb as well as bile salts, vitamins and some drugs

3) Drainage of bile or pancreatic secretions - contain large amount of bicarb

4) Renal tubular acidosis type 1 (distal), 2 (proximal) and 4


How do the kidneys help with renal acid base balance?

1) Reabsorption of filtered bicarbonate
2) Excretion of fixed H+ ions (either as titratable acid or ammonium ions)


Where does reabsorption of filtered bicarbonate occur?

Primarily in the proximal tubule


Key features of reabsorption of filtered bicarbonate

H+ and bicarb are produced in proximal tubule cells from carbon dioxide and water
Carbon dioxide and water combine to form carbonic acid - catalysed by intracellular carbonic anhydrase; carbonic acid dissociates into H+ and bicarbonate anions
H+ secreted into the lumen via the H+/Na+ exchange mechanism in the luminal membrane. Bicarb is reabsorbed

In the lumen, secreted H+ combines with filtered bicarb to form carbonic acid which dissociates into carbon dioxide and water, catalysed by brush border carbonic anhydrase. Carbon dioxide and water diffuse into the cell to start the cycle again

Process results in NET reabsorption of filtered bicarb, but does NOT result in net secretion of H+


What regulates reabsorption of filtered bicarbonate ions in the proximal convoluted tubule?

1) Filtered load
- increases in the filtered load of HCO3- result in increased rates of reabsorption. But if plasma concentration becomes very high (e.g. metabolic alkalosis), the filtered load will exceed the reabsorptive capacity, and bicarb gets excreted in the urine

2) PCO2
- increases in PCO2 result in increased rates of bicarb reabsorption, because the supply of intracellular H+ for secretion is increased; basis of renal compensation for respiratory acidosis
- decreases in PCO2 result in decreases rates of bicarb reabsorption, because the supply of intracellular H+ for secretion is decreased; basis of renal compensation for respiratory alkalosis

3) ECF volume
- ECF volume expansion --> decreased bicarb reabsorption
- ECF volume contraction --> increased bicarb reabsorption (contraction alkalosis)

4) Angiotensin II
- stimulates Na+/H+ exchange thus increases bicarb reabsorption; contributing to contraction alkalosis that occurs secondary to ECF volume contraction


What is fixed acid production?

Fixed H+ produced from catabolism of protein and phospholipids is excreted by 2 mechanisms:

1) Titratable acid
2) Ammonium ions


Excretion of H+ as titratable acid

Amount of H+ excreted as titratable acid depends on the amount of urinary buffer present (usually HPO4-2) and the pK of the buffer

H+ and bicarb are produced in the intercalated cells from carbon dioxide and water. H+ is secreted into the lumen by an H+-ATPase and the bicarb is reabsorbed into the blood ("new bicarb"). In the urine, the secreted H+ combines with filtered HPO4-2 to form H2PO4- which is excreted as titratable acid

Process results in net secretion of H+ and net reabsorption of newly synthesised bicarb. As a result of H+ secretion, the pH of the urine becomes progressively lower. Minimum urinary pH is 4.4

Amount of acid excreted depends on the amount of urinary buffer and the pK of the buffer


How is fixed acid excreted as ammonium ions?

Amount of H+ excreted as ammonium depends on both the amount of synthesised ammonia by renal cells and the urine pH. Three parts of the nephron participate in this exchange:

1) PCT - NH4+ is secreted by Na+/H+ exchanger
2) TAL - NH4+ that was previously secreted is reabsorbed and added to corticopapillary osmotic gradient
3) alpha intercalated cells of collecting duct, NH3+ and H+ secreted into the lumen, combine to form NH4+ and are excreted

Glutamine broken down into NH4+ and glutamate in PCT. Glutamate broken down to bicarb reabsorbed into the blood as "new bicarb". NH4+ is in equilibrium with NH3 and H+. NH3 lipid soluble diffuses down concentration gradient into lumen, H+ secreted by the Na+/H+ exchanger. In the lumen, NH3 and H+ recombine to form NH4+. Portion of this NH4+ excreted directly in urine. Remainder excreted indirectly: first reabsorbed in TAL, then deposited in medullary interstitium, then secreted from interstitial fluid into collecting ducts. NH4+ reabsorption in TAL participates in countercurrent multiplication and is concentrated in interstitial fluid.

Luminal surface of alpha intercalated cells contains 2 transporters that secrete H+ into tubular fluid. NH3 diffuses from high concentration in interstitium into the lumen of collecting duct where it combines with secreted H+ to form NH4+. NH4+ is not lipid soluble and is trapped (diffusion trapping). Source of H+ is carbon dioxide and water. For each H+ produced in the cell and secreted, one new bicarb is synthesised and reabsorbed.


What is type 1 distal renal tubular acidosis?

Main problem is an inability to secrete H+ ions in the distal nephron. This decreases titratable acidity and the excretion of fixed acid as ammonium ions (NH4+) causing the urine pH to become more alkaline. Ammonia, which normally diffuses into the urine from the medullary interstitium, cannot be excreted as ammonium because H+ ions are not being excreted into the urine by a dysfunctional H+ ATPase pump. A lack of H+ ions decreases the excretion of titratable acid

Rx = oral administration of bicarbonate


Causes of type 1 distal renal tubular acidosis

Amphotericin B
Light chains in multiple myeloma
Autoimmune disease (e.g. SLE, RA, SS) sickle cell disease


Other problems associated with distal renal tubular acidosis type 1

Severe acidosis mobilises bone calcium and causes osteomalacia, nephrocalcinosis and urinary stone formation. Diagnosis can be made by a failure to produce an acidic urine even in response to an acid load of NH4Cl.

Hypokalaemia is usually severe.


Pathogenesis of RTA type 2

Renal threshold for reclaiming bicarbonate (reabsorbing filtered bicarbonate) in the proximal convoluted tubule is lowered. When proximal bicarbonate reabsorption fails, large amounts of bicarbonate reach the distal tubule. As the capacity of the distal tubule for bicarbonate reabsorption is limited, there is severe loss of bicarb in the urine causing acidosis. As a result, the plasma bicarb concentration falls and so the filtered load also falls. Eventually the filtered bicarbonate level falls low enough for it all to be reabsorbed in the distal nephron. At this stage an acid urine can excreted and the new low plasma bicarbonate level can be maintained. As a result, a severe acidosis does not occur.

Rx = thiazides to produce volume


Cause of hypokalaemia in RTA type 2

Bicarbonate that is lost takes sodium and water with it, causing volume depletion and triggering aldosterone release --> promotes sodium reabsorption and potassium secretion


Causes of RTA type 2

Carbonic anhydrase inhibitors (MCC)
Primary hyperparathyroidism (incr. PTH --> decreased proximal tubule bicarb reclamation)
Proximal tubule nephrotoxic drugs (e.g. aminoglycosides, valproic acid)
Toxins (e.g. lead, mercury)
Wilson's disease


What is renal tubular acidosis type 4? What is the pathogenesis?

MC RTA in adults - ONLY cause of RTA with hyperkalaemia

Type 4 RTA is due to aldosterone deficiency from destruction of the JG apparatus in the afferent arterioles. Two prominent causes of this destruction are hyaline arteriosclerosis of the afferent arteriole in DM, and acute or chronic tubulointerstitial inflammation (e.g. legionnaire's disease). Destruction of the JG apparatus produces a hyporenic hypoaldosteronism. Since aldosterone controls the Na+-K+ epithelial channels, loss of aldosterone leads to loss of Na+ in the urine and retention of K+ in the blood producing hyperkalaemia. Aldosterone also controls the H+/K+ ATPase pump in the collecting tubule --> less excretion of H+ into the urine in type 4 RTA.


What is the effect of urinary pH on excretion of NH4+?

Decreased urinary pH = increased excretion of NH4+
As pH of urine decreases (becomes more acidic) more of the urinary buffer is present in the NH4+ form and less present in the NH3 form. The lower the luminal concentration of NH3 , the larger the gradient of diffusion of NH3 from medullary interstitial fluid into tubular fluid. So the lower the tubular pH, the greater amount of NH3 diffuses and the more H+ is excreted as NH4+


How does acidosis affect NH3 synthesis?

Rate of NH3 synthesis changes, depending on quantity of H+ that must be excreted. In chronic acidosis, there is an adaptive increase in NH3 synthesis in the cells of the proximal tubule. Mechanism involves a decrease in intracellular pH, which induces enzymes involved in glutamine metabolism.


What is the effect of plasma potassium on NH3 synthesis?

Hyperkalaemia inhibits NH3 synthesis in the proximal convoluted tubule and reduces the ability to excrete H+ as NH4+.

Hypokalaemia stimulates NH3 synthesis and increases the ability to excrete H+ as NH4+.

Effects most likely mediated by exchange of H+ and K+ across renal cell membranes which in turn alters intracellular pH. In hyperkalaemia, K+ enters the cell and H+ leaves. The increase in intracellular pH inhibits NH3 synthesis from glutamine which means less H+ is secreted as NH4+. This is why hyperkalaemia is important in the pathogenesis of type 4 RTA.


Pathogenesis of metabolic alkalosis

Due to loss of H+ or gain of bicarbonate
Respiratory acidosis is compensation


Name some causes of metabolic alkalosis

Hypovolaemic metabolic alkalosis:
- loop and thiazide diuretics
- vomiting

Normovolaemic metabolic alkalosis:
- mineralocorticoid excess (Conn's syndrome, Cushings)


How does vomiting cause a metabolic alkalosis?

There is loss of HCl in vomiting leading to volume depletion

Because of volume depletion, the renal threshold for reclaiming bicarbonate is increased. This occurs because there is increased exchange of H+ ions for Na+ in the Na+/H+ antiporter. Increased H+ ions in the urine allows more of the filtered load of bicarb to be converted into water and carbon dioxide by the brush border which in turn enters the blood. This increase in reclaiming bicarb maintains the metabolic alkalosis in vomiting. This is called a contraction or chloride responsive alkalosis (i.e. infusion of NaCl corrects the metabolic alkalosis)


How does mineralocorticoid excess cause metabolic alkalosis?

Block of ion transporters in the TAL and distal nephron by loop and thiazide diuretics enhances Na delivery to the distal nephron which increases Na reabsorption and excretion of H+, leading to increased synthesis of bicarbonate. Volume depletion also increases proximal tubule reclamation of bicarb which maintains the metabolic alkalosis


Mineralocorticoid excess causing metabolic alkalosis

Increased function of the aldosterone sensitive Na+/H+ epithelial channels in the late distal and collecting ducts leading to increased synthesis of bicarb and metabolic alkalosis. Infusion of normal saline does not correct the alkalosis (chloride resistant)

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