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Genetic renal tubule and metabolic disease

Including: Proximal renal tubular acidosis (RTA); distal RTA; nephrogenic diabetes insipidus Cystinosis; atypical haemolytic uraemic syndrome (HUS); Fabry’s disease; Batter’s syndrome; Gitelman’s syndrome; Liddle’s syndrome


Proximal renal tubular acidosis (RTA)

  • The proximal tubule is responsible for reabsorbing filtered bicarbonate, no acid is excreted
  • Thus, you get bicarbonate wasting and consequent systemic acidosis
  • Genetics of proximal renal tubular acidosis
    • Autosomal recessive if “proximal RTA syndrome”
    • Hypophosphatemic rickets  can be AR or XD
    • Renal glucosuria is AR
    • Cystinosis is AR
    • Wilson’s disease AR
  • Presentation of proximal renal tubular acidosis
    • Normal anion gap acidosis with hyperchloraemia
    • If other features of proximal dysfunction (glycosuria, phosphaturia and aminoaciduria) then termed Fanconi syndrome
  • Investigations of proximal renal tubular acidosis
    • Urine pH <5.3
    • Low serum potassium – as a larger sodium load hits the distal nephron (due to proximal dysfunction) you get hyperaldosteronism and consequent attempts to increase sodium intake and wasting of potassium.
    • Low serum bicarbonate (10-20mmol/L)
    • If tested may find high urinary glucose, phosphate, amino acids, urinary citrate (which all may be low in serum)
    • If you give a bicarbonate challenge then the bicarbonate will overload the already struggling proximal tubule and urinary pH will increase to >7 (done by specialist centre)
  • Treatment of proximal renal tubular acidosis
    • Allow acidosis if mild
    • Thiazide diuretics
    • Potassium bicarbonate
    • Giving sodium bicarbonate (much like the investigative test) serves to make things worse by driving the process as described above, worsening hypokalaemia)


Distal renal tubular acidosis (RTA)

  • Failure of hydrogen ion excretion (alpha intercalated cells of distal nephron)
  • Nephrocalcinosis is a cause, rarely inherited
  • Presentation of distal renal tubular acidosis (RTA)
    • Normal anion gap metabolic acidosis with hyperchloraemia and hypokalaemia
    • Hypophosphataemia (phosphate is used to buffer the acidaemia) – this is leeched from the bones along with calcium and leads to metabolic bone disease, renal stones and nephrocalcinosis
  • Investigations in distal renal tubular acidosis (RTA)
    • Low serum potassium
    • Low bicarbonate <12mmol/L
    • Raised urinary calcium
    • Low urinary citrate (this is a buffer so is used up systemically)
    • Raise urinary pH
    • The commonest causes are autoimmune disease esp Sjorgens so ANA, anti-Ro/La, RhF etc.
    • Specific tests to unmask distal RTA:
      • Furosemide and fludrocortisone challenge OR acid loading test
  • Treatment of distal renal tubular acidosis (RTA)
    • Potassium citrate OR sodium bicarbonate


Nephrogenic diabetes insipidus

  • X-linked dominant or autosomal recessive
  • Causes defects in AVPR2, arginine vasopressin receptor 2 or aquaporin-2
  • Presentation
    • Polyuria and polydipsia (from childhood)
  • Investigations
    •  Measure serum and urine osmolality
      • Raised plasma osmolality with inappropriately dilute urine
    • Definitive testing with water deprivation test
      • After 8 hours of water deprivation if urine osmolality <600 Osmol/kg then desmopressin given
        • If urine concentrates then it is cranial DI, if no effect it is Nephrogenic
  • Treatment
    • Thiazide diuretics (induce mild hypovolaemia ) or NSAIDS (interfere with ADH functioning)
    • Note if not a major problem then conservative management could be indicated


Cystinosis (NOT cystinuria)

  • Autosomal recessive
  • Gene encodes CTNS, lysosomal membrane protein
  • Presentation
    • Renal Fanconi’s syndrome, renal failure in childhood
    • Cystine deposits in all major tissues giving ocular problems, organomegaly, hypothyroidism and diabetes.
  • Treatment
    • Cysteamine (complexes with cystine)


Atypical haemolytic uraemic syndrome

  • Autosomal recessive
  • Pathology
    • Incorrectly coded proteins: Complement factor H; complement factor H-related 1; complement factor H-related 3; CD46; ADAMTS13 (AD)
  • Presentation
    • Thrombocytopenia, haemolytic anaemia and acute renal failure
  • Investigations
    • Bloods including clotting and platelet count, blood film for MAHA, renal function etc
  • Treatment (haematology input)
    • Steroids
    • Plasma exchange
    • Eculizumab (humanized anti-C5 monoclonal antibody) is licensed (blocks complement activation)


Fabry’s disease

  • X-linked recessive (Xq22) lysosomal storage disease
  • Pathology
    • α-galactosidase A protein encoded
  • Presentation
    • Angiokeratoma, FSGS, adult-onset CKD but also cardiac, CNS, ophthalmic and pulmonary disease
  • Treatment
    • Recombinant alpha-Gal A enzyme replacement therapy


Bartter’s syndrome – like a LOOP DIURETIC

  • Autosomal recessive
  • A number of types affecting a host of tubular transport proteins (sodium-potassium-chloride transporter, chloride channel Kb, potassium inwardly rectifying channel; barttin)
  • Pathology
    • Arises from Thick ascending loop of Henle
    • Salt wasting, volume deplete state leads to hyperaldostenorism and hyper-reninism
  • Presentation
    • Hypokalaemic alkalosis, hypercalcuria, polyuria, growth retardation, hypomagnesaemia
    • Note BP is low or normal (as opposed to high) as there is a concurrent prostaglandin increase (PGE) to offset raised angiotensin II (via increased RAAS)
  • Treatment
    • Amiloride and potassium supplementation 1st line.
    • Can treat with NSAIDS to counter prostaglandin synthsis if troublesome
  • NB. Gordon’s syndrome is the polar opposite syndrome and very rare


Gitelman’s – like a THIAZIDE DIURETIC

  • Autosomal recessive
  • Pathology
    • Defect in SLC12A3; thiazide-sensitive sodium-chloride cotransporter
    • Encoding in the distal convoluted tubule
  • Presentation
    • Hypokalaemic metabolic alkalosis, hypocalciuria, hypomagnesaemia and hypotension
    • Note no raise in urinary PGE unlike Bartter’s
  • Treatment
    • Amiloride and potassium supplements



  • Autosomal dominant
  • Pathology
    • Gain of function mutation in epithelial sodium channel (ENaC) in the collecting duct
    • Overexpression leads to huge reabsorption of sodium ions and consequent hypertension
    • Large sodium influx leads the tubular lumen electronegativity leading to potassium influx to correct this – thus hypokalaemic metabolic alkalosis
  • Presentation
    • Hypertension, hypokalaemia and LOW aldosterone.
    • Aldosterone is appropriately suppressed due to sodium uptake being normal (as detected by JGA) – this this is a cause of pseudohyperaldosternoism
  • Treatment
    • Low salt-diet and amiloride


  • Liquorice poisoning:
    • If you eat liquorice you inhibit the function of 11-beta-hydroxysteroid dehydrogenase
      • This enzyme is responsible for inactivating cortisol
    • Cortisol has a potent effect on mineralocorticoid receptors but the normal function of 11-beta-hydroxysteroid dehydrogenase acts to inactivate it prior to working. The concentration of cortisol is significantly greater than that of mineralocorticoids in the body.
    • Thus, if you inhibit 11-beta-hydroxysteroid dehydrogenase by eating a large amount of liquorice (note it must be “natural” liquorice containing glycyrrhizic acid which is the compound inhibiting the enzyme) you allow unopposed cortisol action on mineralocorticoid receptors.
    • In the tubular cells this leads to pseudohyperaldosternoism and the same effects as Liddle’s


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