Lecture 5: Acquired and Congenital Tubular Functional Defects & RTA Flashcards
Fanconi Syndrome is a disease affecting which part of the nephron?
Proximal tubules
In Fanconi Syndrome there will be high levels of what in the urine?
- Glucose
- AA’s
- Uric acid
- Phosphate
- HCO3-
Major clinical features of Fanconi Syndrome?
- Polyuria, polydipsia and hypovolemia
- Growth failure
- Hypokalemia
- Hyperchloremia (due to HCO3- loss)
- Hypophosphatemia/phosphaturia
- Glycosuria + proteinuria/aminoaciduria + hyperuricosuria
Hypophosphatemia associated w/ Fanconi Syndrome is responsible for what serious consequence in children and in adults?
- Children = hypophsphatemic rickets
- Adults = osteomalacia
What type of renal tubular acidosis is due to Fanconi Syndrome?
Type 2 renal tubular acidosis
What are 5 acquired causes of Fanconi Syndrome?
- Maleic acid
- Malignancy
- Multiple myeloma
- Nephrotic Syndrome
- Renal transplantation
What are some medications which can cause Fanconi Syndrome?
- Adefovir and Tenofovir
- Cisplatin (chemotherapy)
- Aminoglycosides (i.e., gentamicin)
- Outdated Tetracycline
- Valproate
What is the therapy for Fanconi Syndrome?
- Replace substances wasted in urine
- HCO3- (can use citrate), phosphate + Vit D
Sx’s of Bartter Syndrome are identical to those of pts taking what drugs?
Loop Diuretcs
Bartter Syndrome is associated with defective transport where in the nephron?
Loop of Henle
How does the neonatal form of Bartter Syndrome present?
- Seen at 24-30 wks of gestation as polyhydramnios; polyuria/polydipsia
- Hypercalciuria after birth
What is the typical onset and presentation for the “classic” form of Bartter Syndrome?
- No noticeable sx’s until around school age (i.e., kindergarten and above)
- Present w/ polyuria/polydipsia
- May also see vomiting and growth retardation
What is used in the treatment of Bartter Syndrome?
- Life-long increases in dietary Na+ and K+
- Potassium-sparing diuretics
- NSAIDs
Why are NSAIDs useful in treating Bartter Syndrome?
- PGE2 directly stimulates renin release and contributes to electrolyte abnormalities
- NSAIDs block and help correct this
Which levels will be elevated in Bartter Syndrome?
- Elevated plasma renin and aldosterone
- Hyperglycemia
- Hyperuricemia
- Increased cholesterol and TAG’s
What is the urine osmolality like in Bartter Syndrome?
Isotonic urine
Which acid base disturbance is present in Bartter Syndrome?
Hypochloremic metabolic alkalosis
Gitelman Syndrome is due to a defect in which transporter and in which part of the nephron?
- Na+-Cl- Symporter
- Distal Tubule
When does Gitelman Syndrome typically present?
More severe in which sex?
- Presents in late childhood or adulthood
- MORE severe in females
Gitelman Syndrome pts have mutations in gene for which cotransporter?
Mimics chronic use of what drug?
- Thiazide-sensitive Na-Cl cotransporter (NCCT)
- Mimics chronic use of thiazide diuretics
Pts with Gitelman Syndrome may develop what at a later age?
HTN
What are major lab findings in Gitelman Syndrome?
What type of acid-base disturbance?
- Hypokalemia + Hyponatremia + Hypomagnesemia (may be severe)
- Hypercalcemia
- Hypochloremic metabolic alkalosis
- Hyperglycemia + Hyperuricemia
- Increased cholesterol and TAGs
*Think about how thiazides work!!!
What kind of urine osmolality can you see with Gitelman Syndrome?
Dilute or concentrated
What is the treatment of Gitelman Syndrome focused on?
Given what?
- Cornerstone = taking in enough NaCl to avoid Na+ depletion
- Providing K+ and Mg2+ supplementation
- Aiming for asymptomatic stable hypokalemia and borderline hypomagnesemia
Effect of NSAIDs on Gitelman Syndrome?
Ineffective
How do calcium levels differ in Gitelman vs. Bartter Syndrome?
- Bartter = HYPOcalcemia/hypercalciuria
- Gitelman = HYPERcalcemia/hypocalciuria
How are urine chloride concentration in a pt w/ Bartter or Gitelman Syndrome vs. someone who secretively takes diuretics?
- Typically >25 mEq/L despite volume contraction in the syndromes
- Pt secretively taking diuretics have variable urine chloride concentration
Failure to respond to what can aid in the diagnosis of Barterr or Gitelman Syndrome?
- Failure of response to thiazide is clue for Gitelman syndrome
- Failure of response to loop diuretic is clue for Bartter syndrome
In Liddle Syndrome (pseudoaldosteronism) which channel is mutated and in which part of the nephron?
- ENaC channels of principal cells
- Collecting duct
Which ion disturbances result in Liddle Syndrome?
Leads to what clinical sx, lab values, and acid-base disturbance?
- ↑ Na+ reabsorption w/ K+ loss
- Producing early and often severe HTN
- Associated w/ LOW plasma renin + LOW aldosterone
- Metabolic acidosis
Liddle syndrome is treated with what combination?
Low sodium diet + K-sparing diuretics
Pseudohypoaldosteronism is caused by failure of what?
Leads to what?
What are the levels of aldosterone like?
- Failure of response to aldosterone leasing to renal tubular acidosis and hyperkalemia
- Aldosterone levels = elevated
Therapy for pseudohypoaldosteornism requires large amounts of what?
Sodium
What is the primary defect in RTA type 1?
Impaired distal H+ secretion
What is the urine pH like in RTA Type 1?
Typically >5.5
Common secondary causes of RTA Type 1?
Autoimmune disorders (i.e., SLE, Sjogrens and RA)
What is the primary defect in RTA Type 2?
Impaired proximal HCO3- reabsorption
Common secondary causes of RTA Type 2?
- In children as part of Fanconi’s syndrome
- In adults as mutliple myeloma or drugs (i.e., tenofovir, ifosfamide, gentamicin, outdate tetracycline)
What is the primary defect in RTA type 4?
Lack of aldosterone or failure of response to it
Which plasma value differentiates RTA type 4 from the other two?
High plasma K+
Common secondary causes of RTA type 4?
- Diabetic nephropathy –> low aldosterone
- Chronic interstitial nephritis
- Drugs –> ACEIs, ARBs, heparin, NSAIDs, spironolactone, others..
Location of defect in RTA type 1 vs. type 2 vs. type 4?
- Type 1 = Distal tubules
- Type 2 = Proximal tubules
- Type 4 = Adrenal
Which RTA presents with the most severe acidosis?
RTA type 1
Which RTA is associated with urinary stone formation due to hypercalciuria w/ low urinary citrate and alkaline urine + bone dimineralization?
RTA type 1
Which 4 findings sum together to equal renal tubular acidosis?
Acidemia + Normal Anion Gap + Normal Serum Cr + No diarrhea
Major consequence of RTA type 1 is low levels of what?
Can lead to what clinical problems?
- Low blood K+
- Leading to extreme weakness, irregular heartbeat, and paralysis
Untreated RTA type 1 leads to what in chidlren and adults?
- Growth retardation in children
- Progressive kidney and bone disease in adults
What is given as treatment for RTA type 1?
Sodium bicarbonate or sodium citrate to tx acidosis
Children w/ RTA type 2 would likely receive what as treatment?
Large doses of potassium citrate, an oral alkali
In RTA type 4, low aldosterone leads to high K+ and a decrease in the synthesis of what?
How does this play a role in the acidosis?
↓ NH3 synthesis by PT
*HCO3- is generated by having NH3 accept H+ –> NH4 to mainatain acid-base homeostasis
What 2 things are done for treatment of RTA type 4?
- Low K+ diet and a loop diuretic (K+-wasting)
- Alter drug doses and/or change drugs (i.e., spironolactone, ACEIs, ARBS, NSAIDs)
Which congenital renal tubule disorder of the nephron is associated with increased plasma renin and aldosterone?
Bartter Syndrome
