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Renal - Gupta > Distal Renal Tubular Disorders > Flashcards

Distal Renal Tubular Disorders Flashcards

1
Q

what are two Na+ wasting disorders in the distal tubule?

A
  • Bartter Syndrome
  • Gitelman Syndrome
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2
Q

What distal tubule disorder causes HTN because of a defect in Na+ transport?

A

Liddle Syndrome

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3
Q

What percentage of Na+ is absorbed in the following areas?

  • Proximal Tubule
  • TALH
  • Distal Tubule
  • Collecting duct
A

Proximal Tubule = 65-70%

TALH = 25%

Distal Tubule = 5%

Collecting Duct = 1-2%

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4
Q

What is targeted by Acetazolamide and where?

A

Carbonic Anhydrase

  • Proximal Convoluted Tubule
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5
Q

What is targeted by Furosemide?

  • other drugs in this class?
A

Bumetanide, Ethacrynic Acid

  • NK2C cotransporter in the TALH
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6
Q

What is targeted by Thiazides?

  • where?
A

NC cotransporter in the Distal Convoluted tubule

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7
Q

What is the targeted by Amiloride?

  • where?
  • other drugs in this class?
A

Amiloride and Triamterene are in the same class

  • ENaC **DCT and CD (I think the CD is more heavily targeted)
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8
Q

What is targeted by Spironolactone?

  • other drugs in class?
  • where?
A

Mineralcorticoid Receptor in the CD Eplerenone

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9
Q

General Bartter Syndrome (applicable to both types)

  • 4 possible mutation?
  • What are some key features of this syndrome?
  • Inheritance?
  • Treatment?
A

Mutations - AUTOSOMAL RECESSIVE:

Bumetanide-sensitive Na+-K+-Cl-cotransporter (NK2C - cotransporter), ATP-sensitive K+ channel (ROMK), Cl- channel A subunit (CLCNKA), Cl- channel B subunit (CLCNKB)

KEY FEATURES

- HYPOkalemia / HYPERaldosteronism => Hyperrreninemia

- HYPOcloremic metabolic alkalosis

  • Kidneys showed hyperplasia of the juxtaglomerular apparatus

- Elevated plasma renin and aldosterone

Treatment: K+ supplements, Mg2+ supplements (if needed)

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10
Q

Differentiate Neonatal Bartter Syndrome and Classic Bartter Syndrome

  • Common Features
  • Key Differences
A

Common Features:

  • Failure to Thrive
  • Hypercalciuria
  • Episodes of Dehydration

Key Differences:
NEONATAL - Polyhydramios, Preterm Delivery, NEPHROCALCINOSIS, HEARING LOSS

Classic - hypercalciurea but NO nephrocalcinosis

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11
Q

Gitelman Syndrome

  • mutation, where?
  • What are some key features of this syndrome?
A

Mutation:
AUTOSOMAL RECESSIVE mutation in NC (thiazide sensitive) Co-transpoerter on the LUMINAL side of the DISTAL CONVOLUTED TUBULE

Features:

HYPOkalemia and Hypochloremic Metabolic Alkalosis
May present with Dehydration and Tetany

HYPOcalicurecemia

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12
Q

What are some key distinguishing features between Bartter’s and Gitelman Syndrome?

  • how does this relate to the nature of their mutation?
A

Bartter’s:

  • HYPERcalciuria
  • Mutation is in the TALH (NK2C, ROMK, or Cl- channel) which is MORE IMPORTANT for Na+ absorption - so deficiency here is more severe and disease is more severe…
  • Failure to Thrive is more common

Gitelman’s Syndrome:

  • *- HYPOcalciuria
  • HYPERmagnesuria**
  • Mutation is in the TSC/ NC cotransporter DCT which is less important for Na+ absorptoin
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13
Q

******All these syndromes of hypochloremic metabolic alkalosis have been associated with hyperplasia of the juxtaglomerular apparatus.

A
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14
Q

********Several other syndromes of hypochloremic metabolic alkalosis (chronic vomiting, diuretic abuse, congenital chloride diarrhea, cystic fibrosis, ingestion of formula deficient in chloride) can mimic Bartter and Gitelman syndrome. How might you distinguish them?

A
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15
Q
  • *Liddle Syndrome**
  • Mutation/inheritance?
  • Clinical Disorder caused by mutation?
  • Treatment?
A

Mutation:
- AUTOSOMEAL DOMINANT Gain of Function mutation in the Beta or Gamma subunit of Epithelial Sodium Channel ENaC

  • *Clinical Disorder:
  • Hyperabsorption of Na+ b/c of XS ENaC leads toHYPOkalemic Metabolic Alkalosis**
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16
Q

What happens when AVP binds the AVP-receptor?
- what specific receptor is most important?

A

AVPR2 receptor aka V2 receptors - its a GPCR

  • causes cAMP release and PKA activation which phosphorylates vesicles and triggers them to fuse with the cell membrane
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17
Q

Why would hyperaldosteronsim and use of Diuretics lead to hypokalemia?

A
  • *Diuretics:**
  • Increase Na+ concentration in the Collecting Duct
  • more exchange of Na+ through ENaC and potassium out of ROMK leads to increased K+ secretion
  • *Hyperaldosteronism:**
  • Increase of ENaC, ROMK, NKA, etc.
  • More channels will favor the already favorable Na+ uptake
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18
Q
  • *Nephrogenic Diabetes Insipidus (NDI)**
  • Mutation(s)/ Inheritance(s)
  • Pathophysiology
  • DDx technique
A

Mutations:

  • *AVPR2 (RECEPTOR MUTATION)** - X-linked point mutations (XQ28)= 90%
  • *AQUAPORIN-2** - Autosomal Recessive = 10%

Pathophysiolgy:

  • *LOW urine Osmolarity** - b/c aquaporins are needed to concentrate the urine
  • *CRAZY HIGH THIRST** - PLASMA osmolarity is HIGH water is not being reabsorbed

DDx:
- This and Central Diabetes Insipidus present the same way except a person with Nephrogenic Diabetes insipidus should be responsive to ADH/DDAVP injection

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19
Q

How do patients with NDI (nephrogenic diabetes insidpidus) present?

  • additional problems in infants?
  • Treatment?
A

Symptoms:

  • Polydipsia, Polyuria, Irritability, Constipation
  • Formula Intolerance with Vomiting, Failure to Thrive, Hyperthermia

Signs:

  • Hydronephrosis
  • Megaureter
  • Bladder Dysfunction

Infants:

  • Severe dehydration can lead to hypoperfusion of the Brain, Kidneys
  • may cause MENTAL RETARDATION and Renal Damage

TREATMENT:

  • *- Abudnant Free Water Intake
  • Low Solute Diet
  • Diuretics**
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20
Q

What diuretics are typically used in nephrogenic diabetes insipidus?
- what is the point of using diuretics to treat these patients?

A

Diuretics:
- Amiloride and Hydrochlorothiazide

Purpose:
- Reduce Obligatory urine ouput to prevent episodes of Dehydration (leading to reduced risk of mental retardation)

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21
Q

What is Glucocorticoid-Remediable Hyperaldosteronism (GRA)?

  • Mutation?
  • Pathiophysiology/disease caused? (hyper/hypo kalemia/natremia etc.)
  • Treatment?
A

Mutation:
- Results from the recombination of the homologous genes for 11-beta-hydroxysteroid dehydrogenase (11betaHSD) and aldosterone synthase

Pathophysiology:

  • Gene pdt. = hybrid molecule that MAKES ALDOSTERONE in response to STRESS
  • causes LOW RENIN HTN and HYPOKALEMIA

Treatment:
- Physiologic doses of Glucocorticoids

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22
Q
  • *Apparent Mineralocorticoid Excess**
  • Mutation
  • Pathophsiology? (hyper/Hypo kalemia/natremia etc.)
  • Treatment?
A

Mutation:
- Kidney isozyme of 11betaHSD

Pathophysiology:

  • increased levels of cortisol in the kidney cross-reacts and **activates the mineralcorticoid receptor
  • causeslow renin HTN, andHYPOKalemia**

Treatment:
- Physiologic Doses of Glucocorticoids

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23
Q

How do Hypoaldosteronism and Pseudohypoaldosteronism come about?
- do they cause hypo or hyperkalemia?

A
  • *Hyperaldosteronism:**
  • Congenital Adrenal Hypoplasia
  • Congenital Adrenal Hyperplasia
  • Autoimmune
  • *Pseudohypoaldosteronism (PHA):**
  • PHA Type I
  • PHA Type II
  • Tubular Injury (obstructive uropathy)

*****BOTH CAUSE HYPERKALIEMIA******

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24
Q

What syndrome is the “mirrow image” of Liddle syndrome?
• Why can we say this?

A

Pseudohypoaldosteronism (PHA) type I
Characterized by:

  • *1. Hyperkalemia
    2. Hyponatremia**
    3. Prone to severe volume depletion and HYPOTENSION
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25
Q

What is the inheritance of PHA type I?
• Treatment?

A
  • *PHA type I - Any Type of Inheritance**
  • *• Recessive Form** = ENaC mutation (explains the hyperkalemia with Hyponatremia)

Treatment:
• High Salt Diet, Prompt Fluid Resusciation (Na+ containing fluids are used in the case of volume depletion), K+ Binding Resin May also be Needed

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26
Q

PHA (pseudohypoaldosteronism) Type II
• AKA?
• Genetic Defect/Pathophysiology?
• Area of filtration system affected?

A

PHA II aka Gordon Syndrome

Genetic Defect:
• WNK1 and WNK4 are mutated leading to INCREASED absorption into the Elecroneutral Na/Cl transporter in the Distal Convoluted Tubule

Pathophysiology:
• Result is excessive Na+ reabsorption and HTN
• K+ secretion is reducedbecause less Na+ is delivered to collecting duct

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27
Q

What syndrome does Gordon Syndrome mirror?
• Treatment for Gordon Syndrome?

A

Gordon’s is the mirror image of Gittelman’s Syndrome

Treatment: THIAZIDE DIURETICS work to treat Gordon’s because they tone down the over active NC co-transporter in the DCT.

28
Q

T or F: Both PHA-I and PHA-II are associated with Hyperchloremic Metabolic Acidosis.

A

True

29
Q

What is a major sign that separates PHA Type I and Type II?

A

PHA Type I - associated with Hypotension
PHA Type II - associated with Hypertension

30
Q

What type of RTA (renal tubule acidosis) is associated with PHA types I and II?
• what defines this type of RTA?

A
  • HYPERchloremic Metabolic Acidosis and HYPERkalemia resulting from a deficiency or an inability to respond to aldosterone action
  • pH of urine may be less than 5.5. during acidosis
31
Q

What are some etiologies of Type IV RTA (renal tubule acidosis)?

Primary Mineralcorticoid Deficiency
• Addisons’s, Adrenal damage, 21-hydroxylase deficiency

Secondary Mineralcorticoid Deficiency
• Hyporeninemic, Hypoaldosteronism ass’d with Diabetic nephropathy, AIDS,

  • *Mineralocorticoid Resistance**
  • *• PHA type I and II**

Renal Tubular Dysfuncion
• Lupus Nephritis, Obstructive uropathy, Hyperkalemic Distal RTA

A
32
Q

What is a means of testing for Type IV Renal Tubular Acidosis?
• what is this test assessing?

A

TTKG - Transtubular Potassium Gradient
• Test assess the Aldosterone activity in the Kidney

33
Q

How is TTKG (transtubular potassium gradient) calculated?
• What are the cutoffs and what do they tell you?

A

TTKG = ([K]urine/[K]plasma)) / (U/P)osm

Hypokalemia TTKG SHOULD BE less than 2 (Denotes Appropriately Decreased Mineralocorticoid activity)

Hyperkalemia TTKG SHOULD BE Greater than 10 (denotes appropriately increased mineralocorticoid activity)

34
Q

Someone is hypERkalemic but has a TTKG of 4.0.
• What general Problem is likely present?

• 3 different problems might you expect?

A

This Person has a TTKG of 4.0 which means that are not concentrating urine well enough in the presence of HYPERKALEMIA

  • This means there must be a general problem with ALDOSTERONE - this is because aldosterone responds to High K+ concentrations by upregulating ENaC, POMK, etc. which aid in K+ excretion
  • Problem could be occuring at 1 of 3 levels:
  1. Aldosterone is never made - Adrenal Insufficiency
  2. Low Renin Secretion - Hyporeninemic Hypoaldosteronism
  3. Tubular Resistance - messed up tubules that can’t respond correctly
35
Q

How would you differentiate Hyperkalemia due to:
• Adrenal Insufficiency
• Hyporeninemic Hypoaldosteronism
• Tubular Resistance

A

Adrenal Insufficiency:
• Plasma Renin will be high but no Aldosterone will be secreted

Hyporeninemic Hypoaldosteronism:
• Low Plasma renin AND low plasma Aldosterone

Tubular Resistance:
• Increased Plasma renin and aldosterone concentration in both

36
Q

T or F: in all cases of Renal Tubular Acidosis the person have hypochloremic metabolic acidosis with an abnormal ion gap.

A

FALSE - RTA = HYPERchloremic metabolic acidosis with a NORMAL PLASMA ANION GAP.

37
Q

What are the ONLY three causes of acidosis with a Normal Plasma anion gap???

A
  1. Renal Tubular Acidosis
  2. Exogenous Chloride (giving someone a bunch of a chloride containing salt e.g. arginine hydrochloride)
  3. GI bicarbonate Loss - DIARRHEA
38
Q

Type II Renal Tubule Acidosis
• cause?
• Associations to KNOW!
• Key features

A

Type II RTA:
• PROXIMAL TUBULE defect leading to decreased Bicarbonate Reabsorption

Association:
• almost always associated with FANCONI SYNDROME

Key Features:
• Pts. can achieve a urine pH less than 5.5 in the face of low bicarb

39
Q

Formula For Anion Gap used to look at acidosis
• Normal for Kids? Adults?

A

Formula: Na+ - (Cl- + CO2)
Normal for Kids: 8-20
Normal for Adults: 10-12

40
Q

What is a key feature to differentiate Type I and Type IV RTA?

A

Type I RTA: can’t concentrate urine past pH 5.5 even in acidosis
Type IV RTA: can concentrate urine below pH 5.5. in acidosis

41
Q

Type I (classical distal) RTA
• cause?
• Inheritance?

A

Cause: Impaired AMMONIUM EXCRETION and impaired excretion of titratable acid

Inheritance: Sporadic or Autosomal Dominant

42
Q

How do patients with Type I RTA present?
• Symptoms
• Lab Findings

A

Symptoms:
• Polyuria, Dehydration, Constipation
• Short Stature, Failure to thrive

Lab Findings:
• HYPERCHLOREMIC, HYPOKALEMIC, METABOLIC ACIDOSIS
• low pH, low serum Bicarbonate, hypokalemia, hyperchloremia
• URINE pH between 6.0 and 7.0
• Decreased urinany citrated excretino and Hypercalciuria

43
Q

What is a common complication of Type I (classical distal RTA)?
• Treatment

A

**Nephrocalcinosis can lead to stones later in life
Patients may also get rickets or osteomalacia

Treatment:**K+ and Bicarbonate Supplements

44
Q

What are some causes of Elevated Anion Gap Acidosis?

A
  • Ketoacidosis
  • Lactic Acidosis
  • Inborn errors of Metabolism (causing acidemias)
  • Poisons (MeOH, Et. Glycol, Salicylates etc.)
45
Q

T or F: Type I (proximal) RTA is almost always associated with Fanconi syndrome (more later)

A

False, Type I (classical distal) RTA is very rare and presents with hypokalemia, hypercalciuria, nephrolithiasis, and failure to thrive

46
Q

T or F: Type IV (hyperkalemic) RTA is a syndrome of aldosterone deficiency or unresponsiveness

A

True

47
Q

T or F: RTA almost never presents with Diarrhea

A

True

48
Q

T or F: Type II (proximal) RTA is almost always associated with Fanconi syndrome

A

TRUE

49
Q

What 4 tests should you look for in RTA?

A
  • Fractional Excretion of Bicarbonate
  • Urine pH
  • Urine Anion Gap
  • U-B PCO2
50
Q

How do you calculate the Fractional Excretion of Bicarbonate?
• how can you differentiate the type of RTA by looking at this?

A

FEHCO3 = (Ubicarb x Pcreatinine) / (Pbicarb x Ucreatinine)

  • Greater than 10-15% in Proximal RTA II
  • Less than 5% in Classical RTA I
  • Less than 5-10% in hyperkalemic RTA IV
51
Q

How can urine pH differentiate the 3 types of RTA?

A

Greater than 5.5 it MUST be classical distal RTA
Less than 5.5 it could be either type II or Hyperkalemic (type IV) RTA

52
Q

How is URINARY Anion gap calculated?
• what does it tell you about the different types of RTA?

A

URINARY anion Gap = UAG = (Na + K) - Cl

• IF GAP is a negative number this indicates the presence of increased ammonium
• UAG POSITIVE in: Type I and IV

• UAG NEGATIVE in: Type II

53
Q

What is U-B pCO2?
• what is it looking for?
• explain the physiology ?
• what is a normal test result?

A

U-B PCO2:
• Patient is given bicarbonate or acetazolamide (carbonic anhydrase inhibitor) causing bicarbonaturia

• IF DISTAL TUBULE can secrete H+ ion then HCO3- is neutralize and CO2 is generated

• Normal people can generate a gradient of 10-15 mmHg

54
Q

What type of RTA lead to a decreased U-B pCO2?

A

Types I and IV because there is less little/no neutralization by H+.

55
Q

Characterize the following for RTA type II:

Finding

Plasma K+

Urine pH

Urine Anion Gap

U-B PCO2

FE HCO3-

Associated Findings

A

Plasma K+: Low

Urine pH: Less than 5.5

Urine Anion Gap: Positive

U-B PCO2: normal

FE HCO3-: Greater than 15%

Associated Findings: Fanconi Syndrome

56
Q

Characterize the following for RTA type I:

Plasma K+

Urine pH

Urine Anion Gap

U-B PCO2

FE HCO3-

Associated Findings

A

Plasma K+: Low

Urine pH: greater than 5.5

Urine Anion Gap: Positive

U-B PCO2: Low

FE HCO3-: Less than 5%

Associated Findings: increased Urinary Ca2+

57
Q

Characterize the following for RTA type IV:

Plasma K+

Urine pH

Urine Anion Gap

U-B PCO2

FE HCO3-

Associated Findings

A

Plasma K+: High

Urine pH: Variable

Urine Anion Gap: Positive

U-B PCO2: Low

FE HCO3-: Less than 5-10%

Associated Findings: Renal Insuffiency in some people

58
Q

WHY IS JUXTAGLOMERULAR HYPERTROPHY SEEN IN BARTTER SYNDROME?

• what is Bartin?

A

Bartter Syndrome = Defective NK2C, ROMK, Cl- channel A or B subunit, Barttin (needed for insertion of Cl- channel of A and B subunits into kidney cells and the inner ear)

Hypertrophy because RENIN is persistently secreted because there is never any response by the tubule cells to the aldosterone that gets produced

59
Q

T or F: people with Bartter syndrome have huge salt cravings.

A

TRUE - they will crave things like pickle juice to make up for their salt intake

***Note: they treat Barter Syndrome pts. with Potassium Supplements to prevent the formation of Renal Cysts***

60
Q

Why do we see polyhydramnios in Bartter Syndrome that presents prenatally?

  • what chemical will be high in the amniotic fluid?
  • why would you give these kids cyclooxgenase inhibitors at birth?
A

These patients lack the channels necessary to concentrate the urine

  • PGE2 will be high in the amniotic fluid
  • COX inhibitors like indomethicin Reduces Urine output so the kids don’t drink as much and fill up on H2O and they will eat more
61
Q

Compare and Contrast the severity of Bartter’s and Gitelman syndrome?

A
62
Q

Gitelman Syndrome is much LESS severe than Bartter’s (because an area of much less Na+ absorption is affected - aka DCT) - people can live with Gitelman and never know that they have it.

A
63
Q

Why do people with Liddle Syndrome present with LOW RENIN?

A

These people have an ENaC GAIN OF FUNCTION leading to increased water absorption and HTN. Renin is down regulated in the face of this HTN.

64
Q

What condition can be caused secondary to Pyloric Stenosis?

A

HYPERALDOSTERONISM - caused by volume depletion leading to increased renin and increased Aldosterone

65
Q

Hyperkalemia is most often associated with kidney failure but in people with PHA type I its also present. Explain this.

A

Disease caused by:

  • Mutation in Mineralcorticoid Receptor (dominant)
  • Loss of Function mutation in ENaC (recessive)

Either Way these patients lack the Na+ and K+ exchange mechanism found in the DCT leading to too much K+ reabsoption

66
Q

What is the MOST important test to run when considering whether someone has RTA?

A

Urine anion Gap

67
Q

What are the Principle Urinary Cations and Anions?

A

Cations: Na+ and K+
Anions: NH4+

Renal - Gupta (17 decks)

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