1. Genetic Disorders of Renal Electrolyte Transport

2. Introduction In the 1950s and 1960s, several inherited
disorders of fluid and electrolyte metabolism were
described in which the principal disturbance
appeared to be a specific functional defect in the
renal tubule

3. Introduction A variety of inherited disorders alter specific renal
epithelial transport functions
This review addresses those in which the
transport of electrolytes or minerals by the renal
tubular epithelium is deranged and the defect has
been attributed to a specific transport protein.

5. Proximal tubular function is altered by
mutations affecting the PHEX (phosphate-
regulating gene with homologies to
endopeptidases on the X chromosome) protein
in X-linked hypophosphatemicRickets.Mutation
of renal ClC-5 chloride channel causes Dent's
diseasesed. In Bartter's syndrome there
are mutations in the genes encoding the
membrane (NKCC2), the ATP-regulated
potassium channel, and kidney-specific chloride
Channel ClC-Kb. These genes are expressed in
the cells of the thick ascending limb.
Mutations in the gene encoding the sodium–
chloride transporter in the distal convoluted
tubule cause Gitelman's syndrome. Mutations
in the gene encoding the calcium-sensing
receptor alter the function of the ascending limb
of Henle's loop and the collecting duct and
cause familial hypocalciuric hypercalcemia.
Activating mutations in the gene encoding the
epithelial sodium channel in Liddle's syndrome
stimulate the reabsorption of sodium chloride in
the collecting duct, and inactivating mutations in
the genes encoding the epithelial sodium
Channel or the mineralocorticoid receptor give
rise to pseudohypoaldosteronism type I.

6. Sodium chloride is reabsorbed
in the thick ascending limb by
the bumetanide-sensitive
sodium–potassium–2-chloride
transporter (NKCC2). This
electroneutral transporter is
driven by the low intracellular
sodium and chloride
Concentrations generated by
Na+/K+–ATPase and the kidney-
specific basolateral chloride channel
(CIC-Kb). The availability of luminal
potassium is rate-limiting for NKCC2,
and recycling of potassium through
the ATP-regulated potassium channel
(ROMK) ensures the efficient
functioning of NKCC2 and generates
a lumen-positive transepithelial
potential.

7. Under normal conditions,
sodium chloride is reabsorbed
by the apical thiazide-sensitive
sodium–chloride transporter
(NCCT) in the distal convoluted
tubule . This electroneutral
transporter is driven by the low
intracellular sodium and
chloride concentrations
generated by Na+/K+–ATPase
and an as yet undefined
basolateral chloride channel. In
this nephron segment, there is
an apical calcium channel and
a basolateral sodium-coupled
exchanger.

8. Mineralocorticoids regulate electrolyte
balance through their action in the
principal cells of the cortical collecting
tubule. The type I mineralocorticoid
receptor binds both aldosterone and
cortisol, but not cortisone. The
specificity of the receptor for
aldosterone is mediated by the type II
kidney isoform of 11ß-hydroxysteroid
dehydrogenase , which
converts cortisol to cortisone. Under
normal conditions, the epithelial
sodium channel is the rate-limiting
barrier for the entry of sodium from
the lumen into the cell . The
resulting lumen-negative
transepithelial voltage drives
potassium secretion from the principal
cells and proton secretion from the
intercalated cells

10. Mutations Affecting the Epithelial Sodium Channel
Liddle’s syndrome:
In 1963 Liddle and colleagues described a
familial syndrome of severe hypertension,
hypokalemia, and metabolic alkalosis that
mimicked hyperaldosteronism

11. Mutations Affecting the Epithelial Sodium Channel
Liddle et al. stated, "The disorder apparently
stems from an unusual tendency of the
kidneys to conserve sodium and excrete
potassium even in the virtual absence of
mineralocorticoids

13. Liddle’s syndrome Affected patients had exceptionally low rates of
aldosterone secretion, hyporeninemia, no
response to spironolactone, and a response to
triamterene and salt restriction.
Studies of the original pedigree revealed an
autosomal dominant inheritance. Mutations
affecting the cytosolic tail of the ß subunit of the
epithelial sodium channel were found in this and
four other, smaller kindreds.

14. Liddle’s syndrome It Manifests in teenage children.
Features include HTN, polyuria, hypokalemic
alkalosis
Na restriction, K replacement and aldactone does
not increase aldosterone

15. Mutations Affecting the Epithelial Sodium Channel
Therapy:
Triametrene.
Renal transplantation normalizes all values
AMCE is an AR syndrome that is due to lack of
type II 11 beta hydroxysteroid dehydrogenase.It
has the same clinical features as Liddle’s
syndrome. The gene is on 16q

16. Mutations Affecting the Epithelial Sodium Channel
Diagnosis is made by finding high urinary
hydrogenated metabolites of
cortisol(Tetrahydrocortisol and
allotetrahydrocortisol).High free cortisol/cortisone
Treatment :
Oral Dexamethasone
Spironolatone, triametrne or amiloride
Transplantation

17. Mutations Affecting the Epithelial Sodium Channel
GRA is an AD syndrome characterized by HTN,
high risk of hemorrhagic stroke, ruptured IC
aneurysm.
The defect affects the 11 Beta hydroxylase .The
2 genes encoding for those 2 enzymes are in
close proximity on chromosome 8

19. Mutations Affecting the Epithelial Sodium Channel
One is encoding for steroid 11 beta
OH(CYP11B1) and the other for
aldosterone(CYP11B2).Hybrid genes might
happen due to crossover from CYP11B1 to
CYP11B2
Aldosterone synthase is now being controlled by
ACTH

20. Mutations Affecting the Epithelial Sodium Channel
This would lead to an overproduction of cortisol
18 oxidation product
Diagnosis: increased urinary aldosterone,18
(OH) cortisol, and 18-oxcortisol.Plasma renin is
reduced.ACTH increases aldosterone
level.Dexamethasone suppresses it. Detection of
the hybrid gene makes the Dx

21. Mutations Affecting the Epithelial Sodium Channel
Treatment :
Low dose Dexamethasone.
Combination dex and aldactone or amiloride is
occasionally necessary

23. Mutations Affecting the Epithelial Sodium Channel
Pseudohypoaldosteronism is a state of
unresponsiveness to aldosterone.
Renal PHA 1: AD and is due to the loss of
function mutation of the gene of MR on
Chromosome 4

25. Mutations Affecting the Epithelial Sodium Channel
PHA 1 is a salt losing syndrome, presenting in the
first weeks of life with hyponatermia, elevated K,
acidosis, failure to thrive. High renin and
aldosterone, high urinary aldosterone metabolites

26. Mutations Affecting the Epithelial Sodium Channel
Treatment with Na supplement.
No response to mineralocortiocid
replacement.Carbenoxolone is also
effective. This disease might resolve with age
Multiple end organ PHA 1 is an AR disorder due
to defective ENaC that is similar to ameloride or
triametrne effect on the distal tubule

28. Mutations Affecting the Epithelial Sodium Channel
Multiple end-organ PHA 1 presents in infancy
with salt wasting and life threatning
hyperkalemia.Markedly elevated Na in all body
secretion
Treatment salt replacement.Hyperkalemia
management.

30. Conditions with Low K, alkalosis and normal BP
Bartter Syndrome:
A syndrome of low K, hypercholremic metabolic
alkalosis and increase urinary Cl, K, N losses
Plasma renin and aldosterone are elevated but
BP is normal
Children with Barrter are subdivided into classical
and neonatal syndrome.

31. Conditions with Low K, alkalosis and normal BP
Barrter syndrome pathogenesis:
It results from Na and Cl wasting in the TALH.
Abnormalities in NKCC2, ROMK, ClC-Kb, and its
beta-subunit(barttin) have been reported.

35. Conditions with Low K, alkalosis and normal BP
Mutations affecting NKCC2
Frame shift nonsense or missense mutations of
the gene for NKCC2, leading to salt wasting
Salt wasting with volume contraction lead to
stimulation of the RAA axis and enhanced Na
absorption of Na by the ENaC in the DCT

36. Conditions with Low K, alkalosis and normal BP
Since Na absorption in the DCT is coupled with K
and H secretion, hypokalemic alkalosis ensues.
The increase PGE2 seen in these patients is not
specific and is due to chronic hypokalemia,
volume contraction and elevated angiotensin II.

37. Conditions with Low K, alkalosis and normal BP
Elevated PGE2 activates the RAA axis and
inhibits ROMK activity, disrupting the K recycling
and NKCC2 function
Elevated PG2 and kallikerein-kinin levels and
chronic volume contraction are responsible for
the lack of high BP despite high plasma
renin.

38. Conditions with Low K, alkalosis and normal BP
There is impaired renal concentration and dilution
and reduced distal Cl reabsorption
The reduced Cl in absorption in the LH inhibits
the voltage driven paracelluluar absorption of Ca
and Mg leading to hypercalciureia and
hypermagnesuria

39. Conditions with Low K, alkalosis and normal BP
Increased calcium losses is associated with
nephrocalcinosis.
Enhanced Mg reabsorption in the DCT, partially
mediated by aldosterone might compensate for
the TALH losses and prevent significant
hypermagnesuria

40. Conditions with Low K, alkalosis and normal BP
Mutation of ROMK, ClC-Kb and Barttin:
ROMK mutation abolishes the K recycling thereby
inhibits NKCC2 function>usually milder form
Inactivating mutations of ClC-KB also results in Cl
wasting and features of barrter syndrome.
Barrtin is a a crucial constituent of CLC-kb
membrane channels in the kidney and ears

41. Conditions with Low K, alkalosis and normal BP
Clinical manifestations
Neonatal Barrter syndrome is characterized by
polyhyramnios, PMD, postnatal polyuria, FTT,
salt craving. High levels of urinary Cl.A variant
with deafness has been described.
Prenatal Dx can be made by high amniotic fluid Cl

42. Conditions with Low K, alkalosis and normal BP
Classic Bartter syndrome
Symptoms begin during the first 2-3 years of life
and are milder than neonatal form.
Symptoms include polyuria, polydipsia, vomiting,
constipation and FTT.

43. Conditions with Low K, alkalosis and normal BP
Diagnosis
The outstanding feature is low K( ),
elevated RA.Low K might cause low aldosterone,
replacing K will unmask this.
Other findings include elevated urinary
aldosterone, FE of Na, K and Cl, low Mg, defects
of the renal diluting and concentrating abilities.

45. Conditions with Low K, alkalosis and normal BP
Molecular diagnosis of Mutations of NKCC2,
ROMK, ClC-Kb and barrtin is now possible by
PCR.
RBC might show increased intracellular Na levels
associated with reduced Na efflux. Might be used
in identifying possible barrter syndrome and
follow response to therapy.

46. Conditions with Low K, alkalosis and normal BP
Treatment of neonatal form:
Correction of the electrolyte disturbances.
KCL
Spironolactone/triametrene
ACE/ conflicting results
Mg replacement
PG inhibitors/NSAIDs.They reduce cortical
perfusion and Na delivery to DCT.It usually
corrects all abnormal findings.

47. Conditions with Low K, alkalosis and normal BP
Outcome
With appropriate therapy outcome is good.
CTI nephropathy with chronic low K and
hypercalicuia.
Declined GFR
Transplant.

48. Conditions with Low K, alkalosis and normal BP
Gitelman Syndrome
AR disease with same clinical features as barrter
but with hypocalciuria and hypomagnesemia.
Defect is in the NCCT in the DCT leading to Na
and Cl wasting

50. Conditions with Low K, alkalosis and normal BP
Hypovolumia leads to activation of RAAS.The
Net Na reabsorption is counterbalanced by K
and H secretion causing hypokalemic alkalosis
7-8% of Na is reabsorbed in the DCT.The
changes is not substantial enough to stimulate
PGE2 production.

51. Conditions with Low K, alkalosis and normal BP
Late presentation, as muscle weakness, cramps
and tetany.No Hx of polyhdramnios.

52. Conditions with Low K, alkalosis and normal BP
Pharmacologic inhibition of the function of the
sodium–chloride transporter by thiazides
stimulates the reabsorption of calcium by the
distal convoluted tubule, and the mutations that
inactivate this transporter in Gitelman's syndrome
presumably cause hypocalciuria in the same
manner

53. Conditions with Low K, alkalosis and normal BP
Thiazides limit the entry of sodium chloride
across the luminal membrane of the cells of the
distal convoluted tubule, and intracellular chloride
continues to exit through basolateral chloride
channels. This hyperpolarizes the cell and
stimulates the entry of calcium through apical,
voltage-activated calcium channels.

54. Conditions with Low K, alkalosis and normal BP
The impairment of sodium entry also lowers the
intracellular sodium concentration and facilitates
the exchange of sodium for calcium across the
basolateral membrane. Thus, thiazides cause
changes in both the luminal entry of calcium and
the basolateral exit of calcium that increase the
reabsorption of calcium in the distal convoluted
tubule, with resultant hypocalciuria.

55. Conditions with Low K, alkalosis and normal BP
Loop diuretics increase urinary magnesium
excretion, whereas thiazides have little effect on
it. Most patients with Gitelman's syndrome have
increased urinary magnesium excretion and
marked hypomagnesemia, but in patients with
Bartter's syndrome, hypomagnesemia is
uncommon and, when present, mild. The
physiologic basis for these differences in
magnesium excretion is not known.

56. Conditions with Low K, alkalosis and normal BP
60 percent of filtered magnesium is normally
reabsorbed in the thick ascending limb, and 5-
10 % is reabsorbed in the distal convoluted
tubule; there is very little reabsorption of
magnesium in the collecting duct. The
mechanisms for the reabsorption of magnesium
in the distal convoluted tubule are similar to those
for calcium

57. Conditions with Low K, alkalosis and normal BP
Volume depletion, metabolic alkalosis, and
vasopressin stimulate magnesium transport in the
distal convoluted tubule, and aldosterone can
potentiate this effect of vasopressin. These
hormonal actions appear to be counterbalanced
by the effects of potassium depletion, which
inhibits the reabsorption of magnesium in the
distal convoluted tubule.

58. Conditions with Low K, alkalosis and normal BP
Thus, the marked salt wasting and aldosterone
stimulation in patients with antenatal or classic
Bartter's syndrome may stimulate the
reabsorption of magnesium in the distal
convoluted tubule, substantially mitigating the
magnesium wasting caused by the transport
defect in the thick ascending limb.

59. Conditions with Low K, alkalosis and normal BP
In Gitelman's syndrome the volume depletion,
metabolic alkalosis, and stimulation of
aldosterone secretion are less severe than in
antenatal or classic Bartter's syndrome. The
effect of hypokalemia may predominate in this
disorder and thus may explain the profound
magnesium wasting that is a cardinal feature of
Gitelman's syndrome.

61. Conditions with Low K, alkalosis and normal BP
Treatment
Mg supplement as MgCl to compensate for the Cl
loss too
K supplement may be needed
NSAIDs.