Potassium

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Potassium

• Dr Anjali Acharya
• Department of Medicine
• Division of Nephrology
• Jacobi Medical Center
• Albert Einstein College of Medicine

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Fredrick V. Osorio and Stuart L. Linus
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Fredrick V. Osorio and Stuart L. Linus
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Calcium Metabolism
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Passive and paracellular Ca2 transport takes
place across tight junctions and is driven by the
electrochemical gradient for Ca2 (blue arrow).
Active and transcellular Ca2 transport is a
three-step process. Ca2 enters through
(hetero)tetrameric epithelial Ca2 channels, TRPV5
andTRPV6, Ca2 bound to calbindin diffuses to the
basolateral membrane. At the basolateral
membrane, Ca2 is extruded via an ATP-dependent
Ca2-ATPase (PMCA1b) and a Na/Ca2 exchanger
(NCX1). The active form of vitaminD stimulates
the individual steps of transcellular Ca2
transport by increasing the expression of the
luminal Ca2 channels, calbindins, and the
extrusion systems.
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Ion transport in loop of Henle
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• TRPV5 knockout mice display profound renal Ca2
  wasting because of impaired active reabsorption
  in DCT of the distal nephron
• TRPV5 expression in the kidney is mainly
  regulated by both PTH and 1,25(OH)2D.
• Parathyroidectomy in rats is accompanied by
  diminished TRPV5, calbindin-D28K, and Na/Ca2
  exchanger protein abundance.
• Nijmegen group clearly established the channel
  TRPV5 as the rate-limiting step in active Ca2
  reabsorption
• They elucidated several interesting extracellular
  factors that may regulate the crucial TRPV5
  channel and play a role in clinical disorders of
  calcium excretion

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• The anti-aging hormone Klotho regulates and
  stimulates TRPV5 activity and calcium transport
  via a novel mechanism
• By modifying its glycosylation status?
• Also, the extracellular pH seems to act as a
  dynamic switch controlling cell surface
  expression of TRPV5.

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• The extracellular calcium-sensing receptor
  (CaSR)-a member of the G protein-coupled receptor
  
• Regulates the secretion of parathyroid hormone
  (PTH) and the reabsorption of tubular fluid
  calcium.
• Activation of the CaR by increased extracellular
  Ca2 inhibits parathyroid hormone (PTH)
  secretion, stimulates calcitonin secretion, and
  promotes urinary Ca2 excretion
• Structural abnormalities of CaSR are responsible
  for different hypo- or hypercalcemic disorders
• Inactivating mutations cause familial
  hypocalciuric hypercalcaemia (FHH) and neonatal
  severe primary hyperparathyroidism (NSPHT), and
• Activating mutations cause autosomal dominant
  hypocalcaemia (ADH)

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Calcium-Sensing Receptor

• The human CaSR gene is located on chromosome
  3q13.321
• The amino acid sequence of the hCaR
• A 1078 amino-acid polypeptide
• Activates multiple G proteins including Gq/11 and
  Gi, and thereby activates
• different signal transduction pathways, depending
  on the cell type
• Activation of the CaR by increased extracellular
  Ca2 leads to inhibition of PTH secretion
• All GPCRs share the signature seven
  transmembrane-spanning (7TM) domain
• Agonist-induced GPCR activation presumably
  involves conformational changes of the
  membrane-spanning helices, altering the
  disposition of intracellular loops and
  Cterminus,and thereby promoting activation of G
  proteins.

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Etiology Of Hypocalcemia

• Hyperphosphatemia
• Intravascular binding 
• Hypercalciuria
• Decreased PTH secretion
• Hypovitaminosis D -poor intake or malabsorption,
  decreased 25-hydroxylation of vitamin D to form
  calcidiol in the liver, increased metabolism to
  inactive metabolites, decreased 1-hydroxylation
  of calcidiol to calcitriol in the kidney, and
  decreased calcitriol action.
• Magnesium depletion Mech-PTH resistance,
  decreased PTH secretion
• Causes-Malabsorption, chronic alcoholism,
  cisplatin, parenteral fluid administration,
  diuretic therapy, aminoglycosides
• Sepsis or severe illness 
• Chemotherapy
• Fluoride poisoning
• Bisphosphonates
• PSEUDOHYPOCALCEMIA

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Treatment of Hypocalcemia

• Symptomatic or may be asymptomatic
• Severity and the underlying cause
• The symptoms paresthesias, tetany, hypotension,
  seizures, and they may have Chvostek's or
  Trousseau's signs, bradycardia, impaired cardiac
  contractility, and prolongation of the QT
  interval.

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Treatment of Hypocalcemia

• Intravenous calcium, (1 to 2 grams of calcium
  gluconate) in 10 to 20 minutes The calcium should
  not be given more rapidly, because of the risk of
  serious cardiac dysfunction, including systolic
  arrest
• followed by a slow infusion of calcium
• Hypomagnesemia

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Hypercalcemia

• Etiology
• Hyperparathyroidism Primary, Sec and tertiary
• Malignancy 
• Thyrotoxicosis 
• Immobilization
• Hypervitaminosis A
• Increased calcium intake 
• Chronic kidney disease 
• Milk alkali syndrome -hypercalcemia, metabolic
  alkalosis, and renal insufficiency
• Hypervitaminosis D -by increasing calcium
  absorption and bone resorption exogenous or
  increased endogenous production of 1,25D
• Thiazide diuretics 
• Rhabdomyolysis and acute renal failure 
• Familial hypocalciuric hypercalcemia  -loss of fn
  mutations in CaSR

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Clinical manifestations of hypercalcemia

• NEUROPSYCHIATRIC DISTURBANCES -anxiety,
  depression, and cognitive dysfunction , lethargy,
  confusion, stupor, and coma
• GASTROINTESTINAL ABNORMALITIES - constipation,
  anorexia, and nausea , pancreatitis and peptic
  ulcer disease
• RENAL DYSFUNCTION- polyuria, nephrolithiasis, and
  acute and chronic renal insufficiency
• CARDIOVASCULAR DISEASE    -shortens the
  myocardial action potential, can cause
  supraventricular or ventricular arrhythmias
• MUSCULOSKELETAL SYMPTOMS 

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Treatment of hypercalcemia

• Acute or chronic
• Severity- serum calcium concentration gt14 mg/dL
• Isotonic saline-initial rate of 200 to 300 mL/h
  that is then adjusted to maintain the urine
  output at 100 to 150 mL/h.
• Loop diuretic
• BISPHOSPHONATES- analogs of inorganic
  pyrophosphate- inhibit calcium release by
  interfering with osteoclast-mediated bone
  resorption
• CALCITONIN
• GLUCOCORTICOIDS 
• Calcimimetics
• Dialysis 

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Phosphate Metabolism
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Electrogenic NaPi-IIa couples 3 Na ions to
uphill movement of one divalent Pi per
transport cycle. One net charge is translocated.
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Phosphate

• The serum phosphate concentration is primarily a
  function of the rate of renal phosphate
  reabsorption
• Molecular components of renal phosphate
  reabsorption
• The Na/Pi co-transporter family mainly consists
  of three different types, but only two are
  expressed in the kidney Type IIa (Na/Pi-2a) and
  type IIc (Na/Pi-2c), which are almost exclusively
  present in the brush border membrane of the renal
  proximal tubular epithelial cells
• Type III Na/Pi transporters are found in the
  basolateral membrane of the renal tubules, where
  they are thought to serve a function of
  regulating intracellular phosphate levels
• Factors affect phosphate transport by influencing
  the Na/Pi co-transporter system (PTH) inhibits
  the Na/Pi co-transporter system-by endocytic
  retrieval of Na/Pi-2a and Na/Pi-2c proteins
• Fibroblast growth factor 23 (FGF-23)
  phosphatonin-stimulating urinary phosphate
  excretion by inhibiting the Na/Pi co-transporter
  system
• Dietary phosphate
• KLOTHO-(named for the Greek Fate purported to
  spin the thread of life),-Klotho is essential for
  endogenous FGF-23 Function.
• Klotho seems to act by converting a protein
  precursor of the receptor for FGF-23 into the
  functional
• receptor.

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HEREDITARY HYPOPHOSPHATEMIC RICKETSWITH
HYPERCALCIURIA (HHRH)

• HHRH is a primary disorder of renal Pi
  reabsorption
• Renal type IIa Na/Pi cotransporter (Npt2) is an
  important determinant of Pi homeostasis
• Growth retardation, bone deformities, renal Pi
  wasting, hypophosphatemia, increased serum levels
  of 1,25(OH)2D and associated hypercalciuria

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Electroneutral NaPi-IIc couples 2 Na ions to
the uphill transport of one divalent Pi. No net
charge transfer occurs
Na
Pi
- - HPO4 2 HPO4
Electrogenic NaPi-IIa couples 3 Na ions to
uphill movement of one divalent Pi per
transport cycle. One net charge is translocated.
Driven by ATP hydrolysis, the NaKATPase maintains
intracellular electronegativity by removing
accumulated Na ions in exchange for K ions.
Basolateral exit of Pi is via an unknown
pathway. Pi then diffuses into blood.
Blood