Tubular Dysfunction and Kidney Tubular Acidosis (KTA)

Liddle syndrome (AKA pseudohyperaldosteronism, pseudoaldosteronism)

• Very rare, but estimates of prevalence vary

• Typically presents in childhood with early-onset hypertension, but sometimes not identified until adulthood

• Pathophysiology:

  • Gain of function mutation results in ↑ number (and thereby ↑ of activity) of epithelial sodium channels (ENaCs) in the principal cells of collecting duct

    • ENaC regulation involves a balance of the insertion and removal of channels in the cell membrane

    • A mutation results in structural alteration of one of the channel's three subunits (α, β or γ), preventing the subunits from being recognized for retrieval and degradation (ubiquitination) by intracellular ubiquitin protein ligase (Nedd4-2)

    • The impairment of retrieval of ENaC from the cell membrane results in an overabundance, and thus an overactivity, of ENaC in the principal cells of the collecting duct

  • ↑ ENaCs → ↑ Na reabsorption from the tubular lumen → ↑ water reabsorption (volume expansion and hypertension) and ↑ K secretion

    • K is exchanged for hydrogen in the distal tubule, so ↑ K secretion → ↑ H+ secretion → metabolic alkalosis

    • Note: ENaC is the channel that is affected by thiazide diuretics

• Lab findings:

  • Hypokalemia

  • Metabolic alkalosis

  • Low renin and low aldosterone

  • Normal sodium level

• Diagnosis:

  • Confirm with genetic testing

    • SCNN1A may not be included in some genetic panels since most cases of Liddle syndrome are caused by mutations in SCNN1B or SCNN1G

• • Low renin AND low aldosterone

• Most common monogenic hypertension in kids (still very rare)

• Inheritance: Autosomal dominant

  • Almost all cases involve SCNN1B (beta) or SCNN1G (gamma) on chromosome 16, but cases involving SCNN1A (alpha) on chromosome 12 have been reported

  • Over 30 mutations have been identified

• Triad of HTN, hypokalemia, metabolic alkalosis

• Genetic testing available: SCNN1A, SCNN1B, SCNN1G

• Treatment: low salt diet, amiloride/triamterene

  • MR antagonists do not work, because the channel itself has a gain of function mutation (ie., it is not a problem of MR upregulation)

• Prognosis: high risk for cardiovascular morbidity and mortality

• At nephron level, kidney can regular water and electrolyte excretion individually to maintain constant extracellular environment

  • Filtration at glomerular level

  • Tubular reabsorption and secretion

• Proximal convoluted tubule

  • Longest segment of the nephron

  • Microvilli increase absorptive surface

  • High capacity transport

  • Bulk of the reabsorption takes place in PCT

  • Na, H2O 60-65%

  • Glucose, phosphate, amino acids, LMW protein

  • Bicarbonate

  • Urea, K, Ca, Mg (K and MG mostly absorbed in distal tubule)

• Specific transport defect

  • Renal glycosuria

  • Hyposphosphatemic rickets

  • PRoximal RTA

  • Cystinuria

  • Lysinuric protein intolerance

  • Aminoacidurias

• Broad PT dysfunction = fanconi syndrome

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• Na-K-ATPase on basolateral membrane

  • 3 Na leave cell in exchange for 2 K, which creates negative intracellular environment

    • Negative intracellular charge is the driving force for sodium-coupled absorption of glucose, phosphate, amino acids

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• Defect in Na-K-ATPase

• Na-P-coupled transporter on apical/luminal side

  • Phosphatonin blocks this

  • Phosphate-regulating gene on X-chromosome: PEX (endopeptidase) degrades phosphatonin

    • Defect in this gene means phosphatonin is constantly active

    • Phosphatonin also blocks activation of vitamin D

    • Will cause hypophosphatemia, low vitamin D, rickets, growth retardation

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• Renal glycosuria

  • SGLT1 and SGLT2 on apical/luminal side

    • SGLT2 is main receptor

  • Glucose reabsorbed until it reaches T max (saturation of the receptor)

    • If glucose load exceeds T max, or reduced affinity of the receptor, then this results in glycosuria

  • Types depend on mechanism:

    • Reduced maximal transport velocity = type A

    • Reduced affinity of receptor = type B

• CO2 absorbs into the proximal cell, where it combines with water (by carbonic anhydrase II) to make bicarbonate and a hydrogen ion

  • Hydrogen ion secreted back into the tubular lumen through hydrogen ATPase pump and sodium-hydrogen exchanger (NHE-3)

  • Bicarbonate is absorbed into the blood on the apical surface with a Na-HCO3 cotransporter (NBC-1)

• Defects in NHE-3, CA II or NBC-1 cause proximal RTA

  • Hyperchloremic, normal anion gap metabolic acidosis

  • Polyuria, polydipsia, vomiting, dehydration, failure to thrive

Megalin protein complex forms an endosome

CIC-5 helps degrade the protein

Chloride proton antiporter -> mutation

Megalin is released

• Malfunctioning of chloride proton antiporter

• Leads to low molecular weight proteinuria

  • B2-microglobulin

  • Retinol binding protein (RBP)

  • PTH also lost

    • Leads to phosphaturia

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• Hypercalciuria - mechanism not entirely clear

• Descending: not much reabsorption happens

• Ascending

  • 25% of chloride (NKCC2)

    • Blocked by loop diuretics

  • Countercurrent multiplier

  • Mg and Ca also rebasorbed

• Distal tubule

  • Na absorbed (NCCT channel)

    • Blocked by thiazide diuretics

  • Ca, Mg also absorbed

• K causes electropositive charge inside the lumen

  • Most Ca, Mg absorbed by passive transport

• Mg, Ca absorbed through Claudin 18, 19

  • Mg

  • Ca absorption also controlled by calcium sensing receptor (CaSR)

    • CaSR inhibits calcineurin and NFATc1, inhibiting claudin-14

• Intracellular active transport of Mg and Ca

  • Mg channel is TRPM6

• Cl goes through NCCT channel

  • CCLA, B on blood side

    • Bartin required for functioning

Large degree of overlap between neonatal and classic Bartter syndrome

Gitelman's

• Magnesium

Collecting duct

• Principal cell

  • Na transport

    • Occurs via ENaC channel

    • Acted on by potassium sparing diuretics

    • Aldosterone dependent

    • Liddle syndrome: overactivation of ENaC

  • K secretion

• Intercalated cell

  • Problems with this cause RTA

• Distal RTA

  • Hyperchloremic normal anion gap acidosis

• Pseudohypoaldosteronism

• Countercurrent multiplication system

  • By the end of the proximal tubule, the tubule is iso-osmolar

  • Descending limb of loop of Henle is impermeable to all but water

  • Thick ascending loop of Henle (TAL): concentration decreases