Acquired and Congenital Tubular Function Defects

Question 1

What are the main urine output findings in Barter Syndrome?

Answer 1

Symptoms of a loop diuretic (furosemide)

Elevated plasma renin and aldosterone

Hypokalemia:

• hypomagnesmia
• hypochloremia —> metabolic alkalosis
• Hypoglycemia

Isotonic urine

Question 2

What type of inheritance is associated with Gitelman syndrome? (22)

Answer 2

AR

Question 3

What is the typical onset of Gitelman Syndrome? (22)

Answer 3

Late childhood or adulthood (AR); life-long

Question 4

What type of diuretic does Gitelman Syndrome mimic? What are the clinical findings as a result of this mimicry?

Answer 4

Mimics thiazide diuretics (Gitelman Syndrome will not respond to thiazide diuretics)

Hypercalcemia

Hypomagnesemia (may be severe)

dilute or concentrated urine

Question 5

How do we treat Gitelman Syndrome? What treatment should be avoided? (24)

Answer 5

Life-long Supplementation:

• Sodium (most important) - want to avoid triggering aldosterone
• potassium - want to achieve stable hypokalemia
• magnesium - want to achieve borderline hypomagnesemia

NSAIDS are infective (defect in distal convoluted tubule after macula densa)

Question 6

Mutation changes in eNaC channel (collecting duct) resulting in incorrect degradation by ubiquitin proteasome leading to increased Na+ reabsorption

Answer 6

Liddle syndrome (Pseudoaldosteronism)

(very rare)

Question 7

Liddle Syndrome is defined by the prescence of ENaC channels that do not degrade by ubiquitin proteasome and are therefore always present. What complications do we see as the result?

Answer 7

increased sodium reabsorption:

• low plasma renin —> low aldosterone
• severe HTN
• metabolic alkalosis

potassium loss (hypokalemia)

Question 8

Renal loss of HCO3- due to failure to reabsorb filtered HCO3- with hyperchloremia

Answer 8

Type 2 RTA (Renal Tubular Acidosis)

Question 9

Distal nephron, reduction in excreted H+ as titratable acid and NH4+ with a decreased ability to acidify urine

Answer 9

Type 1 RTA (Renal Tubular Acidosis)

impairment of α-intercalated cells resulting in no H+ secretion —> now you can’t make new bicarbonate (using NH3+) —> severe acidosis

Question 10

Distal nephron, type of renal tubular Acidosis occurring as a result of hypoaldosteronism with lowered excretion of NH4+ due to inhibition of NH3 synthesis as a result of hyperkalemia.

AKA you don’t have enough ammonia to act as a buffer

Answer 10

Type 4 RTA (Renal Tubular Acidosis)

Question 11

What feature is consistent with all RTA types?

Answer 11

normal anion gap

Question 12

What is the location, acid/base status, and potassium level in RTA type 1?

Answer 12

Distal tubules

Severe acidosis (NAG)

Hypokalemia

Question 13

What is the location, acid/base status, and potassium level in RTA type 2? (31)

Answer 13

Proximal tubule

Severe acidosis (less severe than type 1)

Hypokalemia

Question 14

What is the location, acid/base status, and potassium level in RTA type 4? (31)

Answer 14

adrenal (proximal tubule not putting enough ammonia (H+ acceptor) in the tubule)

mild acidosis (NAG)

Hyperkalemia

Question 15

A general defect of the proximal tubule where there is reduced reabsorption of sodium, glucose, phosphate, amino acids, and bicarbonate

Answer 15

Fanconi Syndrome

These substances show in the urine

Question 16

What are the clinical features of Franconi Syndrome?

Answer 16

1. polyuria and polydipsia
2. Phosphaturia, glycosuria, and proteinuria
3. hypokalemia, hypochloremia (due to HCO3- loss)
4. growth failure (bones)
5. type 2 renal tubular acidosis

Question 17

One of the clinical features of Franconi Syndrome is growth failure in reference to bone health. Describe how this feature presents in children and adults

Answer 17

Children: rickets

Adults: osteomalacia

Question 18

What are the important inherited, acquired, and exogenous factors that increase the risk of Fanconi’s Syndrome?

Answer 18

Cystinosis (AR)

Tyrosinemia type I (AR)

Wilson’s disease (AR)

Nephrotic Syndrome

multiple mylenoma (Bence Jones Proteins)

Heavy metals (mercury)

Question 19

What medications are exogenous factors that can cause Franconi Syndrome due to nephrotoxicity?

Answer 19

1. aminoglycosides (gentamicin)
2. cisplatin
3. valproate
4. gliflozins

Question 20

What is the treatment for Franconi Syndrome?

Answer 20

General rule: replace the substances that are wasted:

• Use citrate instead of bicarbonate (HCO3-) - broken down to bicarb in metabolic processes and the bicarb isn’t lost (because it’s not in the kidney)

Question 21

What is the associated gene mutation and defect in Classic Bartter’s Syndrome (type 3)?

Answer 21

CLCNKB channel (Chloride channel)

Question 22

What is the clinical presentation of Bartter Syndrome?

Answer 22

• No noticeable symptoms until school age (kindergarten age)
• vomiting
• growth retardation
• symptoms similar to loop diuretics (furosemide)

Question 23

What is the treatment for Bartter Syndrome?

Answer 23

• dietary sodium and potassium intake
• potassium-sparing diuretics
• NSAIDs (inhibition of PGE2 from MD)

Question 24

Why are NSAIDs beneficial to a Bartter Syndrome patient?

Answer 24

Because Bartter Syndrome is a defect of the thick ascending limb of Henle high amounts of PGE2 are generated because the defect is prior to the macula densa

NSAIDs can block the high amounts of PGE2 generated

Question 25

In terms of treatment, what is a big differentiator from how Bartter Syndrome is treated vs how Gittelmans is treated?

Answer 25

Gittelmans _cannot_ be treated with NSAIDs

Question 26

Where in the nephron is Gitelman Syndrome associated with?

Answer 26

distal convoluted tubule (NaCl cotransporter)

Question 27

Why in Gitelman Syndrome do we use supplementation to only achieve a **stable hypokalemia** and **borderline hypomagnesemia**?

Answer 27

Supplementation causes GI side effects

Question 28

What are the main differentiators between Bartters Syndrome and Gitelman Syndrome?

Answer 28

Bartter Syndrome: * Produces isotonic urine * hypocalemia/hypercalciuria * give loop diuretic, if they don’t respond = + for Bartter Gitelman Syndrome: * produces dilute or concentrated urine * more benign than Bartter Syndrome * hypercalemia/hypocalciuria * give thiazide, if they don’t respond = + for Gitelman

Question 29

How do we treat Liddle Syndrome?

Answer 29

low sodium diet potassium-sparing diuretics

Question 30

What is the most common RTA type?

Answer 30

RTA Type 4 (Hyperkalemic) * lack of aldosterone or failure to respond * **Proximal tubules not putting enough ammonia in the tubule to act as a buffer (H+ acceptor)**

Question 31

What are the common secondary causes of RTA Type 1 (Classic)?

Answer 31

**Autoimmune disorders** (SLE, RA, Sjogrens)

Question 32

What are the common secondary causes of RTA Type 2 (proximal)?

Answer 32

In children: Franconi Syndrome In adults: * multiple myeloma (bence jones proteins) * drugs (Aminoglycosides: gentamicin, tenofovir)

Question 33

Which type of Renal Tubular Acidosis is the only type to produce Hyperkalemia? What causes this?

Answer 33

RTA Type 4 caused by either **low aldosterone or lack of response to aldosterone** **RTA Type 4 think: proximal tubule not putting enough ammonia into tubule to act as a H+ acceptor**

Question 34

What is the defect in Type 1 RTA? What cascading effect does this have?

Answer 34

impairment of α-intercalated cells resulting in no H+ secretion —\> now you can’t make new bicarbonate —\> resulting acidosis

Question 35

How do we treat RTA Type 1 (classic)?

Answer 35

**Hypokalemia is major consequence** (weakness, irregular rhythm, paralysis): * correct low potassium * correct salt depletion due to acidosis: * give **sodium bicarbonate or sodium citrate (1-2 mEq/kg/day)**

Question 36

What is the defect in RTA Type 2?

Answer 36

Fanconi Syndrome: Bicarbonate is not being reabsorbed in proximal tubule

Question 37

How do we treat RTA Type 2?

Answer 37

Treating directly with bicarbonate is **useless** because the problem is an inability to reabsorb bicarbonate, additional bicarbonate will simply be excreted * **Administer Potassium Citrate (10 - 15 mEq/kg/day) - large dose** * Vitamin D to prevent bone issues * correct low potassium

Question 38

Describe the physiology behind RTA Type 4?

Answer 38

With low aldosterone or lack of response to aldosterone —\> **high K+** —\> **low NH3+** **Synthesis (proximal tubule)** _With low amounts of NH3+ in the proximal lumen, less H+ becomes bound creating NH4+ and you create an acidodic situation_

Question 39

How do we treat RTA Type 4?

Answer 39

**Treat Hyperkalemia** as a result of low aldosterone/lack of response to aldosterone: * low K+ diet (cabbage, low K+ fruits) * Loop diuretic (Furosemide)