Tubular Disorders of Electrolyte Regulation

7/30/2019 Tubular Disorders of Electrolyte Regulation

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Tubular disorders of electrolyte regulation

Dr.Rahul

CH-2


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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


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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


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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


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Classical Bartter syndrome

Insidious onset in infancy

Present with failure to thrive

Nephrocalcinosis is typically absent(hypercalciuria to lesser extent)


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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


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1997

LiftonBS III = mutation of gene on chr 1 = ClCNkb

2001 LandauBSND = mutation of gene on chr1 = Barttin


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BARTTERS SYNDROME


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Neonatal Bartters syndrome


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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


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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.


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Cyclooxygenase-2 is highly expressed in maculadensa

Inhibition by nimesulide improvement of

hyperprostaglandinuria, secondary

hyperaldosteronism, and hypercalciuria


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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


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CLASSIC BARTTERS SYNDROME


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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


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Polyuria related hydroureteronephrosis Formation of medullary cysts due to prolonged

hypokalemia


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Biochemical findings

Hypokalemia

Hypochloremia

Metabolic alkalosis

Exceptionally may present with metabolic acidosis Hyperuricemia

Rarely,

Polycythemia Hypercalcemia

Hypophoshatemia


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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


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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


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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


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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


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Gitelman syndrome


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History

Reported in 1966

a new familial disorder characterized byhypokalemia and hypomagnesemia in two adultsisters


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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


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Pathophysiology

NaCl co-transporter defect : NaCl wasting,

Hypovolemia, Metabolic alkalosis, stimulation of

Renin-angiotensin axis

Hypocalciuria

Hypermagnesuria


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Hyperreninism

Hyperaldosteronism

Normal urinary excretion of prostaglandin

No abnormal finding on renal biopsy

Hypermagnesuria

Hyperkaluria

Hypocalciuria


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Calciuric response to furosemide is blunted, which

differentiates from Bartters syndorme, who exhibit

increased calciuric response to furosemide


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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


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GLUCOCORTICOID REMEDIABLE ALDOSTERONISM


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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


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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


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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


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LIDDLE SYNDORME


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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


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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


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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


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APPARENT MINERALOCORTICOID EXCESS


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Clinically and biochemically similar to Liddles

syndrome

Autosomal recessive

Mutations in HSD11B2 gene on Chr.16 Deficiency of 11B HSD


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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%


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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


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Secondary pseudo hyperaldosteronism

Acquired syndrome

Chronic ingestion of licorice

Extract of Glycyrrhiza glabra root potent inhibitor of

11B HSD2


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RENAL TUBULARHYPERKALEMIA


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Hyperkalemic states:

1. Hyperreninemic Hypoaldosteronism

2. Hyporeninemic Hypoaldosteronism

3. Primary type 1 pseudohypoaldosteronism

4. Type 2 pseudohypoaldosteronism(Gordonssyndrome)


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MINERALOCORTICOID DEFICIENCY


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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


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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


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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


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Apparent mineralocorticoid unresponsiveness

A.K.A Pseudohypoaldosteronism


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Inherited abnormalities of renal Na transport

Renal Type 1 pseudohypoaldosteronism

1. Renal

2. Multiple

Secondary Type 1 pseudohypoaldosteronism

Type 2 pseudohypoaldosteronism(Gordonssyndrome)


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Primary type 1 pseudohypoaldosteronism

Renal tubular unresponsiveness to action of

aldosterone

Salt wasting

Hyperkalemia Metabolic acidosis

Elevated renin and aldosterone


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Renal type 1:


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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


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Hyponatremia

Hyperkalemia

Metabolic acidosis

Renal biopsy finding usually negative Increased renin and aldosterone

Lack of improvement despite large doses ofmineralocorticoids


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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


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Plasma aldosterone levels remain elevated but renin

levels normalise

Due to development of autonomous tertiary

hyperaldosteronism


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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


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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


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Poor response to NaCl supplementation

Rectal administration of exchange resins

Dietary reduction of K+ intake

Improvement with age is less apparent


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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


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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


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Short stature in children

Hypertension in adults

Hyperkalemia

Hyperchloremic metabolic acidosis Hyporeninemic hypoaldosteronism

Normal GFR

Hypercalciuria with formation of calcium oxalate

stones


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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


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REFERENCE

Documents

Tubular Disorders of Electrolyte Regulation