Renal Tubule Acidosis, Sodium Disorders

Question 1

what are the causes of normal anion-gap metabolic acidosis? (there’s an acronym)

Answer 1

DRAASHS:
Diarrhea
Renal tubule acidosis
Addison’s / Adrenal insufficiency

[iatrogenic:]
Acetazolamide
Spironolactone
Hyperalimentation
Saline infusion

Question 2

in a normal kidney, urine anion gap will be ____ in response to acidosis

Answer 2

health kidney will excrete more ammonium, causing urine anion gap to be negative

Question 3

what 2 steps are required for renal net acid excretion?

Answer 3

1. proximal HCO3- reabsorption
2. distal H+ excretion via intercalated cells

Question 4

which proximal transporter is responsible for H+ secretion to allow for bicarbonate reabsorption in the kidneys?

Answer 4

NHE: secretes H+ in exchange for Na+ (Na H Exchanger)

H+ reclaims HCO3- via H2CO3, carbonic anhydrase coverts this back to CO2 and H2O

this H+ does not participate in excretion of daily acid load, because it is reclaimed as HCO3-

Question 5

what will happen if you administer bicarbonate to a patient with Type 2 renal tubule acidosis?

Answer 5

Type II (proximal) RTA: defect in proximal HCO3- reabsorption

administer bicarb —> urine bicarb and pH will increase

Question 6

what are the common etiologies of Type I (distal) renal tubule acidosis?

Answer 6

Type I (distal) RTA: impaired H+ excretion due to defective H+-ATPase

etiologies:
- autoimmune (Sjogren, SLE, primary biliary cholangitis)
- chemotherapy
- amphotericin

Question 7

Pt presents with unexplained normal anion gap metabolic acidosis. PMH includes autoimmune disorder. Urine pH is high (>5.5) and urine anion gap is positive. Serum K+ is low.

What is the likely diagnosis?

Answer 7

Type I renal tubule acidosis: distal impairment of H+-ATPase, inability to acidify urine

K+ wasting because without H+ excretion, Na+ reabsorption via ENaC (which generates negative lumen potential) will drive K+ secretion alone

Question 8

why is Type I RTA associated with hypercalciuria/calcinosis?

Answer 8

Type I renal tubule acidosis: distal impairment of H+-ATPase, inability to acidify urine

acidosis leads to decreased tubule calcium reabsorption —> increased urine calcium —> body responds by increasing calcium resorption from bone

acidosis + hypokalemia increases citrate reabsorption in the proximal tubule (citrate in urine normally binds calcium to form soluble complex) —> calcinosis

Question 9

any alteration that impairs distal renal Na+ reabsorption will tend to produce metabolic:
a. acidosis
b. alkalosis

Answer 9

disruption in distal Na+ reabsorption produces metabolic acidosis + hyperkalemia

(Type IV renal tubule acidosis - hypoaldosteronism)

recall Na+ reabsorption is in exchange for H+ excretion, and acidosis is linked to hyperkalemia

Question 10

in which patients is Type IV RTA most common?

Answer 10

Type IV RTA: hypoaldosteronsim (due to low renin)

most common in patients with mild/moderate renal impairment, such as diabetes mellitus

can also be caused by NSAIDs, angiotensin inhibitors

Question 11

which Na+ channel is found at:
a. proximal tubule (PCT)
b. TAL (thick ascending)
c. distal convoluted tubule (DCT)
d. cortical collecting (CCT)

Answer 11

a. PCT: NHE (Na+/H+)
b. TAL: NKCC (Na+/K+/Cl-)
c. DCT: NCC (Na+/Cl-)
d. CCT: ENaC (Na+)

Question 12

Bartter syndrome

Answer 12

autosomal recessive defect in NKCC (Na/K/Cl) in TAL (thick ascending) —> Na+ wasting tubulopathy

impaired ability to concentrate urine —> polyuria/polydipsia, hypokalemia/metabolic alkalosis, high urine calcium

volume depletion secondary to impaired NaCl reabsorption —> RAAS —> increased K+ and H+ secretion —> metabolic alkalosis

Question 13

impaired ability to concentrate urine due to autosomal recessive defect in NKCC (in TAL)

Answer 13

Bartter syndrome

—> polyuria, polydipsia
—> hypokalemia, metabolic alkalosis
—> high (or normal) urine calcium

Question 14

Gitelman syndrome

Answer 14

autosomal recessive defect in NCC (Na+/Cl- cotransporter) in DCT —> low urine calcium, magnesium wasting (but preserved ability to concentrate urine)

increased Ca2+ reabsorption favored by low intracellular Na+

volume depletion secondary to impaired NaCl reabsorption —> RAAS —> increased K+ and H+ secretion —> metabolic alkalosis

low Mg+ and K+ —> muscle cramping, weakness, tetany

Question 15

autosomal recessive defect in NCC (Na/Cl cotransporter) in the DCT, leading to low urine calcium and magnesium wasting

Answer 15

Gitelman syndrome: AR defect in NCC (in distal convoluted tubule)

diagnosis in late childhood/young adulthood

low Mg+ and K+ —> muscle cramping, weakness

*increased Ca2+ reabsorption favorited by low intracellular Na+

Question 16

Bartter syndrome vs Gitelman syndrome

Answer 16

Bartter: AR defect in NKCC (TAL), inability to concentrate urine, elevated urine Ca2+, presents infancy-adulthood [2 T’s to match 2 C’s]

Gitelman: AR defect in NCC (DCT), preserved ability to concentrate urine, low urine Ca2+, presents late childhood-young adulthood [1 T to match 1 C]

both cause volume depletion secondary to impaired NaCl reabsorption —> RAAS —> increased K+ and H+ secretion —> metabolic alkalosis

Question 17

explain how Type IV RTA can cause hyperkalemia and metabolic acidosis

Answer 17

Type IV RTA: loss of ENaC function in cortical collecting duct - aldosterone resistance

—> loss of negative lumen potential —> retention of K+ and H+ —> hyperkalemia, metabolic acidosis

Question 18

Liddle syndrome

Answer 18

autosomal dominant GOF in ENaC Na+ transporter in principle cells —> Na+ retention

presents in ages 15-30 with resistant HTN due to volume expansion

low renin/aldosterone, hypokalemia (—> arrhythmias), metabolic alkalosis

Question 19

autosomal defect in ENaC within principle cells, presenting in ages 15-30 with resistant HTN due to volume expansion and low renin and aldosterone levels

Answer 19

Liddle syndrome: AD ENaC GOF mutation (principal cells), ages 15-30 with resistant HTN and Na+ retention

low renin and aldosterone

—> hypokalemia (arrhythmias), metabolic alkalosis

Question 20

if a patient has resistant HTN + unexplained hypokalemia and metabolic alkalosis AND renin and aldosterone levels are low AND there is family history, what are you thinking?

Answer 20

Liddle syndrome: AD ENaC GOF mutation (principal cells), ages 15-30 with resistant HTN (due to volume expansion)

low renin and aldosterone

—> hypokalemia (arrhythmias), metabolic alkalosis

Question 21

if a patient has HTN + unexplained hypokalemia and metabolic alkalosis AND low renin / aldosterone but NO family history, what are you thinking?

Answer 21

SAME (syndrome of apparent mineralocorticoid excess): autosomal recessive deficiency of 11beta-hydroxysteroid dehydrogenase, which prevents cortisol —> cortisone metabolism

—> HTN, hypokalemia, low renin, low aldosterone

can also be acquired via glycyrrhizic acid (natural licorice) which inhibits above enzyme

Question 22

which channels are affected by each of the following:
a. Liddle syndrome
b. Bartter syndrome
c. Gitelman syndrome

Answer 22

a. Liddle syndrome: high ENaC activity

b. Bartter syndrome: low NKCC activity (like a loop diuretic)

c. Gitelman syndrome: low NCC activity (like a thiazide diuretic)