RTA

Question 1

What is RTA?

Answer 1

This describes a group of hyperchloraemic metabolic acidosis occurring secondarily to an abnormality in urinary acidification

Question 2

What is the principle abnormality in RTA?

Answer 2

Loss in bicarb results in low serum Na conc

Question 3

How is the prinicple abnormality compensated for? Relate to anion gap.

Answer 3

Need to compensate electrochemical loss by increasing serum chloride to restore electroneutrality. Reflected in the anion gap as it remains unchanged

Question 4

How is bicarbonate reabsorbed in the PCT?

Answer 4

By excreting an H+ via a Na-H antitransporter (NHE3). HCO3 combines with H to make carbonic acid to dissociate into water and CO2 (catalysed by carbonic anhydrase IV). CO2 and water is reabsorbed passively. Recombine in the PT cell to make carbonic acid via carbonic anhydrase II. Cabonic acid dissociates into HCO3 and H. 3xBicarb enters blood with 1xNA (NBC1)

Question 5

Describe type I RTA

Answer 5

Characterised by the inability of the distal tubular secretion of H+ and, thus, inability to lower pH<5.5 in systemic acidaemia. It can be inherited or acquired disorder.

Question 6

Biochemical features of RTA I

Answer 6

Hypokalaemia (renal potassium wasting to maintain electroneutrality), nephrocalcinosis, and urolithiasis

Question 7

What causes RTAI to lose ability to secrete H+?

Answer 7

Two mechanisms
Secretory
- inability to create and maintain H+ gradient across luminal membrane

Back-leak
- inability to secrete H+ remains but a gradient cannot be maintained due to H+ back diffusion

Question 8

What is the difference between primary and secondary forms?

Answer 8

Primary inherited

Secondary acquired

Question 9

Primary RTAI

Answer 9

Autosomal dominant
- mutation in SLC4A1 which encodes for the AE1 anion exchanger that mediates the bicarbonate exit from the alpha-intercalated cells

Autosomal recessive
- utation in ATP6V1B1 or ATP6V0A4 which encodes for the B1 and A4 subunits of the H+ ATPase

Question 10

Secondary RTAI

Answer 10

Due to a range of diseases or drugs. Caused by

• autoimmune disease: systemic lupus erythematosus, rheumatoid arthritis
• tubulointerstitial disease: chronic interstitial nephritis, obstructive uropathy
• hypergammaglobulinemia: multiple myeloma, chronic liver disease
• Drugs: lithium, NSAID, antivirals

Question 11

What is incomplete distal RTA?

Answer 11

Do not present metabolic acidosis, but lack the ability to produce acidified urine following acid load

Question 12

What causes incomplete distal RTA?

Answer 12

Increased excretion of NH4+ balances acid base abnormality caused by renal inability to excrete H+.
Low urinary citrate and elevated calcium promote nephrocalcinosis and urolithiasis

Question 13

What is RTA II?

Answer 13

Proximal RTA characterised by the impaired bicarbonate reabsorption in the proximal tubules and subsequent self-limiting urinary loss

• has an intact H+ secretion meaning ability to form acidified urine is present.
• Inherited or aquired

Question 14

Primary RTAII

Answer 14

• mutations in SLC4A4 which encodes a NBC1, a mutation which associate with short stature and ocular abnormalities
• Others: inherited conditions causing RTAII are cystinosis, tyrosinaemia, glactosaemia, Wilsons disease

Question 15

Secondary RTAII

Answer 15

Here a range of toxins (heavy metals), drugs and other disorders (multiple myeloma, vit D deficiency) can cause the development of RTA II.

Question 16

What is RTAIV?

Answer 16

Distal RTA with mineralocorticoid deficicency.

• aldosterone deficiency or the tubular resistance to its actions
• urine acidification is intact, but exretion of NH4 is subnormal
• present with hyperkalaemia

Question 17

Cause of reduced aldosterone and resistance in RTAIV?

Answer 17

Reduced aldosterone production causing the disorder can be due to hyporeninaemic hypoaldosteronism (renal disease, NSAIDs), angiotensin pathway disruption (ACEi), adrenal insufficiency or inherited disorders.

Resistance caused by ENaC inhibition (spironolactone, eplerenone) or pseudohypoladosteronims type I

Question 18

What needs to be excluded when diagnosing RTA?

Answer 18

Common causes of normal anion gap metabolic acidosis such as GI bicarbonate loss

Question 19

What biochemical tests are useful in investigating RTA?

Answer 19

U&E to make an anion gap

- Anion gap is used to estimate urinary NH4 excretion

Question 20

What does the anion gap tell you in RTA investigations?

Answer 20

• negative AG indicates increase NH4 excretion - seen in RTA II

Question 21

How is the urine osmolar gap used?

Answer 21

Same function as AG: estimate NH4 excretion

- urine osmolar gap>100 indicates increased urinary excretion of NH4+ - thus RTA II

Question 22

What calculation can be done using a paired serum and urine sample?

Answer 22

Fractional bicarbonate excretion

- >10-15% indicates RTA II

Question 23

How is the trans-tubular potassium gradient used in RTA diagnosis?

Answer 23

Used to estimate the glucorticoid activity in suspected type 4 RTA

• > 10 in hyperkalaemia
• <7 suggest lack of aldosterone

Question 24

What dynamic function test is available?

Answer 24

Ammonium chloride loading test: Test kidneys ability to deal with acid load

• Ammonium chloride is administered orally over 2h. Urine will be collected every hour for 6 hours for pH measurement
• RTAI has urine pH <5.5

Question 25

Describe the management of RTA

Answer 25

RTA specific as different sections of the tubular are affected

• Type I: administering bicarbonate 1-2mmol/Kg/day
• Type II: administering bicarbonate 5-15mmol/Kg/day together with potassium supplements
• Type IV: Treat mineralocorticoid def with fludrocortisone or mineralocorticoid resistance with diuretics and potassium restrictions