Download - Tubular Disorders of Electrolyte Regulation
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
1/70
Tubular disorders of electrolyte regulation
Dr.Rahul
CH-2
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
2/70
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
3/70
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
4/70
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
5/70
Hypokalemic states:1. Neonatal Bartters syndrome
2. Classic Bartters syndrome
3. Gitelman syndrome
4. Glucocorticoid remediable aldosteronism
5. Pseudohyperaldosteronism
6. Liddles syndrome
7. Apparent mineralocorticoid excess syndrome8. Secondary pseudohyperaldosteronism
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
6/70
Bartter-like salt losing tubulopathies
History
In 1962, Frederic Bartter
Reported two patients with
Hypokalemia and Metabolic alkalosis
Normal blood pressure despite high aldosteroneproduction
Hyperplasia of juxtaglomerular complex
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
7/70
Works of McCredie, Fanconi, Dillion Two quite distinct clinical presentations of BS
identified
Neonatal variant of BS
The most severe form
Polyhydramnios, premature delivery
Growth retardation
Marked hypercalciuria leading to
nephrocalcinosis
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
8/70
Classical Bartter syndrome
Insidious onset in infancy
Present with failure to thrive
Nephrocalcinosis is typically absent(hypercalciuria to lesser extent)
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
9/70
Contribution by geneticists
1996
Simon et alGitelman disease = mutation of gene on Chr 16
= NaClneonatal variant of BS (BS I) = mutations of
gene on Chr 15 = NaK2Cl cotransporter
LiftonBS II = ROMK channel
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
10/70
1997
LiftonBS III = mutation of gene on chr 1 = ClCNkb
2001 LandauBSND = mutation of gene on chr1 = Barttin
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
11/70
BARTTERS SYNDROME
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
12/70
Neonatal Bartters syndrome
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
13/70
Pathophysiology
Hyperprostaglandin E2 syndrome Increased renal and systemic prostaglandin E2
production was indicated by symptoms such as
fever, diarrhea, vomiting , osteopenia and
generalised convulsions and elevation of urinaryexcretion of prostaglandin E-M metabolite
Now, molecular biology findings show abnormalities
in genes and prostaglandin abnormalities appear as
secondary phenomenon
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
14/70
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
15/70
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
16/70
Urine output may be as great as12-50 ml/kg/hr till4 to 6 weeks after birth
Some have distinct facies Thin, small muscles,
triangular face, large and protruding eyes, drooping
mouth Failure to thrive, but appropriate therapy is followed
by satisfactory growth
Systemic manifestations such as fever, secretory
diarrhea,convulsions and increased susceptibility toinfections have been reported.
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
17/70
Cyclooxygenase-2 is highly expressed in maculadensa
Inhibition by nimesulide improvement of
hyperprostaglandinuria, secondary
hyperaldosteronism, and hypercalciuria
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
18/70
Aim: Correct dehydration and electrolyte imbalanceand clinical stabilization with catch up growth
Administration of indomethacin in early postnatal
period may be unnecessary but also dangerous ,
given risk of necrotising enterocolitis. At 4 to 6 weeks, indomethacin may be beneficial as
it neutralizes amplifying effect of prostaglandins.
Sodium, potassium and chloride supplementation
give additional control Low decrease in GFR as a result of chronic
tubulointerstitial nephropathy can occur
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
19/70
CLASSIC BARTTERS SYNDROME
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
20/70
Type 3 Bartters syndrome Mutation of gene on chr 1 = ClCNkb
Polyuria, polydipsia,vomiting,constipation,salt
craving, failure to thrive and tendency to dehydrationin first 2 years of life
Fatigue, muscle weakness and cramps with
recurrent episodes of carpopedal spasm in late
childhood
History of maternal hydramnios and premature
delivery
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
21/70
Polyuria related hydroureteronephrosis Formation of medullary cysts due to prolonged
hypokalemia
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
22/70
Biochemical findings
Hypokalemia
Hypochloremia
Metabolic alkalosis
Exceptionally may present with metabolic acidosis Hyperuricemia
Rarely,
Polycythemia Hypercalcemia
Hypophoshatemia
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
23/70
Increased urinary excretion of Na,K,Cl Normal or high urinary Na excretion
GFR is normal in early stages but may become
impaired in untreated patients due to chronic
hypokalemia
Hyperreninemia
Hyperaldosteronism
Increaased urine excretion of prostaglandins
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
24/70
Role of indomethacin
Corrects sodium depletion, and suppressangiotensin production
Inhibits secretion of prostaglandins
Corrects hyperactivity of adrenergic system
Side effects:
Nausea and vomiting
Peptic ulcerHematopoietic toxicity
Liver damage
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
25/70
Therapy
Potassium supplementation Addition of spirinolactone(10 to 15 mg/kg/day) or
triamterene(10 mg/kg/day)
Prostaglandin synthesis inhibitors:
1. Indomethacin(2 to 5 mg/kg/day)2. Acetylsalicylic acid(100 mg/kg/day)
3. Ibubrofen(20 mg/kg/day)
Addition of magnesium salts should be considered
when hypomagnesemia present as it may
aggravate K+ wasting
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
26/70
Long term prognosis remains guarded Lack of rigorous therapeutic control lead to slow
progression to chronic renal failure
Maintainance of indomethacin therapy is mandatory
during renal biopsy to avoid bleeding due to
defective platelet aggregation
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
27/70
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
28/70
Gitelman syndrome
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
29/70
History
Reported in 1966
a new familial disorder characterized byhypokalemia and hypomagnesemia in two adultsisters
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
30/70
Familial hypokalemia-hypomagnesemia
Mutation in gene locus SLC 12A3 on chr.16, which
encodes thiazide sensitive NaCl cotransporter in
DCT
In many cases, diagnosis is made only in adult life
Transient episodes of weakness and tetany
Salt craving, nocturia and polydipsia
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
31/70
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
32/70
Pathophysiology
NaCl co-transporter defect : NaCl wasting,
Hypovolemia, Metabolic alkalosis, stimulation of
Renin-angiotensin axis
Hypocalciuria
Hypermagnesuria
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
33/70
Hyperreninism
Hyperaldosteronism
Normal urinary excretion of prostaglandin
No abnormal finding on renal biopsy
Hypermagnesuria
Hyperkaluria
Hypocalciuria
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
34/70
Calciuric response to furosemide is blunted, which
differentiates from Bartters syndorme, who exhibit
increased calciuric response to furosemide
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
35/70
Therapy
Magnesium salts alone
MgCl2 is best compensates for ongoing urine Cl
losses and less often followed by diarrhea
Potassium salts and antialdosterone drugs rarely
needed
Long term prognosis excellent
Sustained Mg supplementation remains necessary
to reduce risk of tetanic episodes
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
36/70
GLUCOCORTICOID REMEDIABLE ALDOSTERONISM
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
37/70
Also called Familial Hyperaldosteronism type 1
Rare cause of low renin hypertension
Autosomal dominant
Chimeric gene formed at meiosis between adjacent
genes on Chr.8 encoding 11 B-hydroxylase and
aldosterone synthase, involved in cortisol and
aldosterone synthesis
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
38/70
Aldosterone excess due to aldosterone being under
control of ACTH rather than angiotensin-2
Diagnosis:
Dexamethasone suppression test Plasmaaldosterone below 4 ng/dl postdexamethasone due
to ACTH suppression
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
39/70
Therapy
Potassium retaining diuretic such as spirinolactone
or amiloride
Administration of dexamethasone may also
ameliorate hypertension, but prolonged use notrecommended given its deleterious effects on growth
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
40/70
LIDDLE SYNDORME
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
41/70
Mutation of genes encoding beta or gamma subunit
of amiloride sensitive epithelial sodium
channels(ENaC)
SNCC1B and SNCC1G genes on Chr.16
Autosomal dominant but some are sporadic
Hypertensive individuals in successive generations
very suggestive ofLiddles syndrome
Lack of hypotensive effect of spirinolactone or
dexamethasone administration also suggestive of
Liddles syndrome
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
42/70
Present in infancy or early childhood
Polyuria, polydipsia, failure to thrive
Hypertension, nephrocalcinosis
Medullary cysts in few cases
Improvement observed after triamterene but not afteradministration of spirinolactone
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
43/70
Therapy
KCL supplementation
Triamterene (10 mg/kg/day)
Therapeutic trial with spirinolactone or
dexamethasone should be considered given clinical
similarity with 11B-HSD deficiency
Catch up growth rarely occurs, and may remain
significantly growth retarded
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
44/70
APPARENT MINERALOCORTICOID EXCESS
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
45/70
Clinically and biochemically similar to Liddles
syndrome
Autosomal recessive
Mutations in HSD11B2 gene on Chr.16 Deficiency of 11B HSD
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
46/70
In normal state, cortisol is converted to cortisone by11B-HSD
High intrarenal cortisol concentration facilitatesbinding to type 1 receptor resulting in AME
Diagnosis:
Measuring ratio of cortisol to cortisone metabolites Only 0 to 6 % in AME , whereas normal conversion
is 90-95%
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
47/70
Hypertension
Suppressed renin and aldosterone secretion
Hypercalciuria and nephrocalcinosis are consistentwith the disease
Therapy:
Mineralocorticoid receptor blocker : Spirinolactone
Daily dose ranges between 2-10 mg/kg/day
Thiazide to improve hypercalciuria and aid inlowering BP
Renal transplantation completely normalizes the
disease
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
48/70
Secondary pseudo hyperaldosteronism
Acquired syndrome
Chronic ingestion of licorice
Extract of Glycyrrhiza glabra root potent inhibitor of
11B HSD2
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
49/70
RENAL TUBULARHYPERKALEMIA
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
50/70
Hyperkalemic states:
1. Hyperreninemic Hypoaldosteronism
2. Hyporeninemic Hypoaldosteronism
3. Primary type 1 pseudohypoaldosteronism
4. Type 2 pseudohypoaldosteronism(Gordonssyndrome)
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
51/70
MINERALOCORTICOID DEFICIENCY
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
52/70
Hyper reninemic hypoaldosteronism:
1. Adrenal insuffiency (Addisons disease)
2. Aldosterone biosynthetic defect such as 21 OH
lase or 11B OH lase
Salt wasting
Recurrent episodes of dehydration and salt wasting
Hyperkalemia
Failure to thrive
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
53/70
Hypo reninemic hypoaldosteronism:
1. Chronic renal insuffiency
2. Chronic nephropathy secondary to Lupus nephritis
3. Chronic nephropathy secondary to Methylmalonic
acidemia
Damage to juxtaglomerular apparatus
Impaired formation of renin
Reduced activity of adrenergic system and
prostaglandins
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
54/70
Avoidance of renin suppressing agents( Beta
blockers, Calcium channel blockers, NSAIDS)
Avoidance of K-retaining agents(Amiloride,
Spirinolactone, Heparin, Trimethoprim)
Furosemide may be administered
No specific therapy
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
55/70
Apparent mineralocorticoid unresponsiveness
A.K.A Pseudohypoaldosteronism
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
56/70
Inherited abnormalities of renal Na transport
Renal Type 1 pseudohypoaldosteronism
1. Renal
2. Multiple
Secondary Type 1 pseudohypoaldosteronism
Type 2 pseudohypoaldosteronism(Gordonssyndrome)
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
57/70
Primary type 1 pseudohypoaldosteronism
Renal tubular unresponsiveness to action of
aldosterone
Salt wasting
Hyperkalemia Metabolic acidosis
Elevated renin and aldosterone
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
58/70
Renal type 1:
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
59/70
Renal type 1:
Starts in early infancy
More common form
Autosomal dominant
Failure to thrive and polyuria
Weight loss
Vomiting and dehydration
Maternal hydramnios may be seen
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
60/70
Hyponatremia
Hyperkalemia
Metabolic acidosis
Renal biopsy finding usually negative Increased renin and aldosterone
Lack of improvement despite large doses ofmineralocorticoids
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
61/70
Treatment
NaCl supplementation(3 to 6 g/day)
Expansion of ECF volume results in increase in tubular
flow and NaCl delivery to distal nephron , creating
favorable gradient for K secretion despite lack of
mineralocorticoid action
Improvement beyond 1 or 2 years age, due to maturation
of proximal tubular transport and improvement in renal
tubular
Older children with renal PHA1 are asymptomatic when
eating normal salt intake
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
62/70
Plasma aldosterone levels remain elevated but renin
levels normalise
Due to development of autonomous tertiary
hyperaldosteronism
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
63/70
Multiple type 1:
More severe salt wasting
Poorer outcome
Death during neonatal period
Pathophysiology: Defective sodium transport in kidney, lung, colon
and exocrine glands
Mutation in epithelial Na channels(ENaC) allelic to
Liddles syndrome
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
64/70
Loss of channel activity with ensuing renal and rectal
Na loss
Dysfunction of ENaC of respiratory epithelium and
impaired bacterial killing due to increased NaClconcentration
High incidence of LRTI may cause confusion with
cystic fibrosis Sweat electrolytes and salivary electrolytes elevated
Not corrected by administration of mineralocorticoids
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
65/70
Poor response to NaCl supplementation
Rectal administration of exchange resins
Dietary reduction of K+ intake
Improvement with age is less apparent
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
66/70
Secondary type 1 pseudohypoaldosteronism
Salt wasting and hyperkalemia seen in:
1. Unilateral renal vein thrombosis(Partial tubular
insensitivity to aldosterone )
2. Neonatal medullary necrosis3. Acute pyelonephritis
4. Obstructive uropathy
Type 2 pseudo hypoaldosteronism
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
67/70
Type 2 pseudo hypoaldosteronism
(Gordons syndrome)
Autosomal dominant
Mutations in WNK 1- 4 genes
Gain of function mutation in WNK kinases in distal
tubules
Increased tubular reabsorption of NaCl Expansion of ECF volume
Suppressed renin and aldosterone
Attenuation of mineralocorticoid induced K+ and H+
secretion
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
68/70
Short stature in children
Hypertension in adults
Hyperkalemia
Hyperchloremic metabolic acidosis Hyporeninemic hypoaldosteronism
Normal GFR
Hypercalciuria with formation of calcium oxalate
stones
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
69/70
Therapy with Diuretics
Return of BP to normal
Rise in renin and aldosterone
Correction of metabolic acidosis and hyperkalemia
Hydrochlorthiazide (1.5-2 mg/kg/day) is best, as it
also corrects hypercalciuria
-
7/30/2019 Tubular Disorders of Electrolyte Regulation
70/70
REFERENCE