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Renal Pathophysiology Disorders of Potassium Homeostasis

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Renal Pathophysiology Disorders of Potassium Homeostasis Powered By Docstoc
					Potassium Homeostasis & Disorders


                   Kevin Ho, M.D.
         Assistant Professor of Medicine
             Renal-Electrolyte Division
    University of Pittsburgh School of Medicine
                Potassium Distribution in the Body

                                                          Intracellular [K+]
                                          Na+              120-150 meq/L
Potassium distribution in body fluid                                       2 K+
compartments                                                                            3 Na+
  Total body K+ stores: 50-55 meq/kg                K+
   body weight (3500-4000 meq K+
   total)                                                   Em = -90mV

                                                          Extracellular [K+]
  Extracellular fluid compartment: 2%
                                                           3.5-5.0 meq/L
   [K+] = 3.5-5.0 meq/L (50-100 meq K+)
                                                Resting membrane potential
  Intracellular fluid compartment: 98%
                                                Nernst equation
   [K+] = 120-150 meq/L                              EK = RT ln [K]o
                                                          zF     [K]i
  Large cellular K+ (and Na+)
   concentration gradients are                  Steady-state equation
   maintained by the Na,K-ATPase                    Vm = RT ln r[K]o + b[Na]o
                                                           zF   r[K]i + b[Na]I
                                                r = 3:2 Na/K active transport
                                                b = 0.01 relative permeability of Na+ to K+
         Potassium Gradient and Cellular Functions


Cellular functions
 Primary determinant of cell resting
  membrane potential
 Substrate for membrane transport
  processes
                                                     Intracellular [K+]
 Determinant of cell volume
                                          Na+         120-150 meq/L

Changes in transmembrane                                              2 K+
potassium gradient                                   K +                        3 Na+
                                                K+
 Alter cell membrane resting potential
 Alter neuromuscular excitability        K+           Em = -90mV
     Cardiac conduction & cardiac
      pacemaker rhythmicity                          Extracellular [K+]
                                                      3.5-5.0 meq/L
     Neuronal function
     Vascular smooth muscle tone
     Skeletal muscle function
 Impair cell membrane transport
  processes
            Extracellular Potassium Concentration and
                     Cell Membrane Potential




     +30                        Membrane potential  ln [K]o
                                                        [K]i
       0


      -30                                           Depolarization
mV                                   Hyperpolarization
      -60                                                    Threshold

      -90                                                    Resting

     -120
                 Normal        Hypokalemia    Hyperkalemia

            Hypokalemia hyperpolarizes excitable tissues
            Hyperkalemia depolarizes excitable tissues
                      Potassium Homeostasis

   The regulation of potassium homeostasis can be divided into two
   main processes:
       External Balance: The regulation of total body potassium content
       through alterations in potassium intake (e.g. dietary) and excretion
       (e.g. renal, GI)
       Internal Balance: The regulation of the distribution of potassium
       between intracellular fluid (ICF) and extracellular fluid (ECF)
       compartments
           Intake

External
Balance
                                          Internal

                                    K+
                                          Balance

                                                        K+
                    3.5-5.0 meq/L
              Extracellular Fluid (ECF)
                                                          120-150 meq/L
      Excretion                                       Intracellular Fluid (ICF)
                  External Potassium Balance:
                Intake & Renal K+ Reabsorption

Potassium intake                         Renal potassium reabsorption
     Dietary intake = 50-150 meq/day      Proximal tubule
      (3-9 grams KCl/day)                     Majority of solute and H2O
                                                transport
     IV KCl, hyperalimentation, drugs        Passive processes
     Blood products                          65% filtered K+ load
                                            Thick ascending limb
       K+ Intake                              25% filtered K+ load
                                              Active + passive processes
                                              Na-K-2Cl cotransporter
                                            Cortical and medullary collecting ducts
                                              Intercalated cells (Type A + Type B)
         Renal                                Active process
    K+ Reabsorption                           H-K-ATPase

                   Proximal Tubule

                   Thick Ascending Limb

                   Collecting Duct
                          Renal Potassium Handling


                                    DCT              CCD

Cortex
                PCT
                                            10-15%
         K+
          H2O    K+
                              K+                     K+
                 H2O
          65%     S3          TAL                                Outer Stripe
                              K+            25%
                                           K+        K+
Medulla




                        35%                                 OMCD
Outer




                              K+
                 tiDL                      K+                   Inner Stripe
                                                     K+
                                           K+
                                     35%
                                                K+
                              tiAL                        IMCD
                                                K+
Medulla




                                                K+
Inner
                  External Potassium Balance:
                 Excretion & Renal K+ Secretion

Potassium excretion
 Renal K+ handling
    Excretion of 90-95% dietary K+ intake
    Only renal K+ excretion is tightly
     regulated
    Regulation of final urinary K+ content
     occurs in the collecting duct
    Variable urinary K+ loss: 5-25 meq/day
     to >400 meq/day                           K+ Intake

Renal K+ Secretion
 K+ secretion in the collecting duct
    Principal cells                             Renal
    Apical K+ channels                       K+ Secretion



                                                           Collecting Duct
                          Renal Potassium Handling


                                    DCT              CCD

Cortex
                PCT
                                            10-15%
         K+
          H2O    K+
                              K+                     K+
                 H2O
          65%     S3          TAL                                Outer Stripe
                              K+            25%
                                           K+        K+
Medulla




                        35%                                 OMCD
Outer




                              K+
                 tiDL                      K+                   Inner Stripe
                                                     K+
                                           K+
                                     35%
                                                K+
                              tiAL                        IMCD
                                                K+
Medulla




                                                K+
Inner
             Distal Renal K+ Secretion:
      The Principal Cell in the Collecting Duct

Major determinants of K+ secretion in the collecting duct
  Potassium-secreting cell in the collecting duct is the principal cell
  K+ gradient across the membrane is generated by the Na+-K+-ATPase
  K+ permeability of the apical membrane is determined by K+ channels
  Na+ reabsorption by Na+ channels results in a lumen-negative potential
   difference across the apical membrane
  These K+ and Na+ transport processes are stimulated by aldosterone


     ENaC Channel
                 Na+
                                                    
                                             2 K+

          Tubule                                          3 Na+
          Lumen
                            K+

     ROMK Channel                Principal Cell

                Apical                                  Basolateral
            Distal Renal K+ Reabsorption:
      The Intercalated Cell in the Collecting Duct

Major determinants of K+ reabsorption in the collecting duct
  The potassium-absorbing cell in the collecting duct is the intercalated cell
  The intercalated cell is also responsible for H+ secretion
  Potassium reabsorption by the intercalated cell is an active process which
   is mediated by the apical membrane H+,K+-ATPase


           Apical                                      Basolateral
                                                         3 Na+
             H+                                    
                                         2   K+
                          K+
                                                          K+
                                                         HCO3-
             H+
                                           Cl-
                           Intercalated Cell              Cl-
Regulation of Renal Potassium Secretion




     Peritubular Factors

        Plasma potassium concentration
        Aldosterone
        Extracellular pH

     Luminal Factors

        Distal tubular flow rate
        Sodium delivery
        Anion composition
             Regulation of Potassium Secretion:
                 Plasma K+ Concentration




              Urinary K+ Secretion
                                                                    High K Diet




                                                                   Normal Diet



                                     3   4       5         6      7             8
                                             Plasma [K +] (meq/L)


 Potassium intake  potassium adaptation
      Urinary K+ secretion increases with a high K+ diet
Adaptive changes   K+ secretion in the collecting duct
       principal cell Na+,K+-ATPase activity +  Na+ and K+ channel transport
       area of basolateral membrane in principal cells
       K+ reabsorption by intercalated cells
Both increased plasma K+ and aldosterone are required for maximal
adaptation
                                                (Stanton BA, Giebisch G: Am J Physiol 243:F487-F493 (1982))
Morphological Alterations in Potassium Adaptation



                                                 Low-K+ Diet




        Normal Diet
                                                High-K+ Diet




                           (Stanton BA: Am J Physiol 257:R989-R997 (1989))
            Aldosterone Effects on the Principal Cell


Regulation of K+ secretion by
principal cells in the collecting duct
is the primary basis for K+
homeostasis
  Na+ reabsorption via Na+ channels
                                           (-)
   (ENaC) results in a lumen-negative                       3 Na+
   transcellular potential difference
  Lumen-negative potential difference
                                           Na+                          2 K+
   favors K+ secretion via K+ channels       ENaC            Aldo
                                                              MR
   (ROMK)                                                                Aldo
                                                    K+
Aldosterone                                 ROMK
  Aldosterone stimulates K+ secretion
   by principal cells in the collecting
   duct
  Aldosterone binds to an intracellular
   receptor, which when activated
   functions as a transcriptional                   Principal Cell
   regulator  synthesis of
   aldosterone-induced proteins
            Distal Renal K+ Secretion:
   Effects of Aldosterone on the Principal Cell

       Apical        Basolateral          Apical          Basolateral
                                                          R
     (-)                             (-)      R- Aldo           Aldo
                                                                 (+)
                        K+                                K+
    Na+                             Na+                           Na+
                              Na+   Na+
                                                          K+
     K+                              K+                           Na+
                                     K+            AIPs
    Lumen                           Lumen


                Basal                        + Aldosterone

 basolateral Na+,K+-ATPase activity
   K+ entry and Na+ gradient for apical Na+ reabsorption

 apical membrane Na+ and K+ channels
   Na+ reabsorption via apical Na+ channels generates a lumen-negative
   electrical potential difference across the apical membrane favoring K+
   secretion into the lumen of the collecting duct via K+ channels
       Regulation of Potassium Secretion: Plasma pH




Extracellular pH                                                                                        pH 7.57




                                               K+ excretion meq/L filtrate
Changes in extracellular pH
produce reciprocal shifts in H+ and                                          6
K+ between the extracellular fluid                                                                      pH 7.41
and intracellular fluid compartments
                                                                             4                          pH 7.17
  Acidemia decreases intracellular
   [K+] in principal cells and decreases
   K+ secretion                                                              2
  Alkalemia increases intracellular
   [K+] in principal cells and increases
   K+ secretion
                                                                                  3       5         7
                                                                                 Plasma   [K+]   meq/L




                                      (Stanton BA, Giebisch G: Am J Physiol 242:F544-F551 (1982))
Regulation of Renal Potassium Secretion




     Peritubular Factors

        Plasma potassium concentration
        Aldosterone
        Extracellular pH

     Luminal Factors

        Distal tubular flow rate
        Sodium delivery
        Anion composition
               Regulation of Potassium Secretion:
                   Distal Tubular Flow Rate



Distal flow rate

Increase in distal flow rate favors
K+ secretion




                                         Distal K+ secretion
                                                               0.5              High K+ diet
      Enhances luminal K+ gradient
      Increases distal Na+ delivery 
        Na+ reabsorption  lumen-                             0.3
       negative potential difference                                                    Control K+ diet
      Response dependent on high                              0.1
       K+ diet                                                                                 Low K+ diet
       ( plasma [K+] +  aldosterone)
                                                                              10          20          30
       Flow-dependent K+ secretion
       mediated by maxi-K Ca2+-                                                Distal flow rate
       activated) K+ channel



                                                                     Brenner BM. Brenner & Rector’s The Kidney.
                                                                     Philadelphia: W.B. Saunders Co., 1996:391
            Regulation of Potassium Secretion:
            Na+ Delivery to the Distal Nephron



          K+ Secretion




                         Distal Flow       Distal [Na+]
 Increasing distal tubular Na+ delivery stimulates distal tubular Na+
  reabsorption resulting in the generation of a lumen-negative potential
  difference which stimulates K+ secretion
 Increased distal flow is usually associated with increased distal Na+
  delivery (e.g. intravascular volume expansion, diuretic administration)
 Effect of Luminal Anions on Potassium Secretion




Distal luminal anion
composition
 Substitution of another anion
  for Cl- (poorly reabsorbable
  anion)   lumen-negative
  potential difference favoring K+                            Na+
  secretion                           HCO3-        Na+              
                                                                        K+
                                     (-)      HCO3-
     HCO3-
                                                         K+
     Acetoacetate
     b-hydroxybutyrate                    HCO3-
     Carbenicillin
     Hippurate
                 Transtubular Potassium Gradient


                                         Transtubular potassium
                                         gradient
TTKG = CCDK / PK
                         CCDK            Clinical index of K+ secretion in
                CCDOsm   CCDOsm          the cortical collecting duct
CCDK = UK x
                 UOsm             PK       TTKG = ratio of the
                                  POsm      estimated urinary K+
CCDOsm = POsm                               concentration in the cortical
                                            collecting duct to the
                                  H2O       plasma K+ concentration
                POsm
CCDK = UK x
              UOsm                         CCDK is estimated by
                                   H2O      correcting the UK for water
                         UOsm               reabsorption in the
          UK / PK        UK                 medullary collecting duct
TTKG =
         UOsm / POsm                       Potassium depletion:
                                            TTKG < 2.5
                                           Potassium loading:
                                            TTKG > 10
                      Potassium Homeostasis

   The regulation of potassium homeostasis can be divided into two
   main processes:
       External Balance: The regulation of total body potassium content
       through alterations in potassium intake (e.g. dietary) and excretion
       (e.g. renal, GI)
       Internal Balance: The regulation of the distribution of potassium
       between intracellular fluid (ICF) and extracellular fluid (ECF)
       compartments
           Intake

External
Balance
                                          Internal

                                    K+
                                          Balance

                                                        K+
                    3.5-5.0 meq/L
              Extracellular Fluid (ECF)
                                                          120-150 meq/L
      Excretion                                       Intracellular Fluid (ICF)
   Potassium Homeostasis: Internal Balance




Internal Balance
 Regulation of K+ distribution between the intracellular and extracellular
  compartments is responsible for the moment-to-moment control of the
  extracellular potassium concentration

 Internal balance is the net result of two cellular processes:

   (1) Cellular potassium uptake
      Mediated by the Na+,K+-ATPase

   (2) Cellular potassium secretion
      Mediated by K+ channels which determine the K+ permeability of
       the cell membrane
Internal Balance: Physiologic Factors




 Internal Balance
   Insulin
   Catecholamines
             Potassium Homeostasis: Insulin



               [K+]             Pancreas



                                                 Insulin
                                  Liver
               [K+]                                  K+
                                 Muscle


 Insulin stimulates the cellular uptake of potassium via an increase
  in Na+,K+-ATPase activity
 Insulin and potassium are components of a regulatory loop
      splanchnic K+ concentration stimulates pancreatic insulin secretion
     Insulin stimulates K+ uptake by the liver and muscle returning serum
      [K+] to normal
       Potassium Homeostasis: Catecholamines


  Change in Plasma Potassium   2.5   Exercise        Recovery


                               2.0


                               1.5
           (mmol/L)




                               1.0

                               0.5
                                                                             Propranolol
                                0                                            Control



                                           10   20         30          40
                                                 Minutes

Catecholamines stimulate the cellular uptake of potassium via
b2-adrenergic receptors by increasing Na+,K+-ATPase activity

                                                          (Williams et al: N Engl J Med 312:823-827 (1985))
Internal Balance: Pathophysiologic Factors




   Internal Balance
     Acid-Base Disturbances
     Plasma Tonicity
     Cell Lysis & Cell Proliferation
            Potassium Homeostasis
  Internal Balance: Pathophysiologic Factors I

Acid-Base Disturbances
   Changes in extracellular pH produce reciprocal shifts in H+ and K+
   between extracellular and intracellular fluid compartments
     Metabolic acid-base disturbances have a greater effect than
      respiratory disturbances
     Metabolic acidoses due to organic acids (ketoacidosis, lactic
      acidosis) have smaller effects than do acidoses due to mineral
      acids




                 H+           H+               H+            H+
                 K+           K+               K+           K+


            Acidemia                       Alkalemia
            Potassium Homeostasis
 Internal Balance: Pathophysiologic Factors II



Plasma Tonicity
   Increases in plasma tonicity  fluid shifts from the intracellular to the
   extracellular compartments and K+ exits the intracellular compartment
   along with water via solvent drag



               Increased Plasma Tonicity




                              H2O K+
            Potassium Homeostasis
 Internal Balance: Pathophysiologic Factors III




Cell Lysis & Cell Proliferation
  With cell lysis intracellular K+ is released into the extracellular space
   yielding an increase in extracellular [K+]
  With rapid cellular proliferation, K+ is rapidly taken up by proliferating
   cells causing extracellular potassium to fall
              Hyperkalemia
               Plasma [K+] > 5.0
Hyperkalemia may be the result of disturbances
in external balance (total body K+ excess) or in
internal balance (shift of K+ from intracellular to
extracellular compartments)
Hyperkalemia: Disorders of External Balance

                    Renal K+ excretion

  Excessive             Acute & chronic
  K+ intake              renal failure




               Distal tubular    Distal tubular
                   flow           dysfunction




                       Mineralocorticoid
                          deficiency
   Hyperkalemia: Disorders of External Balance


Excessive Potassium Intake
     Oral or Parenteral Intake

Decreased Renal Excretion
   Acute and Chronic Renal Failure
   Decreased Distal Tubular Flow
     Volume depletion
     Decreased effective arterial blood volume (CHF, cirrhosis)
     Drugs altering glomerular hemodynamics with a decrease in GFR
      (NSAIDs, ACE inhibitors, ARBs)
   Mineralocorticoid Deficiency
     Combined glucocorticoid and mineralocorticoid (adrenal insufficiency)
     Hyporeninemic hypoaldosteronism (diabetes mellitus)
     Drug-induced (ACE inhibitors, ARBs)

   Distal Tubular Dysfunction
     Disorders causing impaired renal tubular function with
       hyporesponsiveness to aldosterone (interstitial nephritis)
     Potassium-sparing diuretics (amiloride, triamterene, spironolactone)
Hyperkalemia: Disorders of Internal Balance




        Insulin deficiency
        b2-Adrenergic blockade
        Hypertonicity
        Acidemia
        Cell lysis
       Clinical Manifestations of Hyperkalemia



Clinical manifestations result primarily from the depolarization of
resting cell membrane potential in myocytes and neurons
   Prolonged depolarization decreases membrane Na+ permeability through
   the inactivation of voltage-sensitive Na+ channels producing a reduction
   in membrane excitability

Cardiac toxicity
  EKG changes
  Cardiac conduction defects
  Arrhythmias

Neuromuscular changes
  Ascending weakness, ileus
EKG Manifestations of Hyperkalemia




                      Normal
                  +
Increasing Serum K




                      Peaked T-wave

                      Wide QRS Complex
                      Shortened QT Interval
                      Prolonged PR Interval

                      Further Widening of QRS Complex
                      Absent P-Wave

                      Sine-Wave Morphology
                      (e.g. Ventricular Tachycardia)
    Medical Treatment of Hyperkalemia




Membrane Stabilization
 IV calcium

Internal Redistribution
 IV insulin (+ glucose)
 b-adrenergic agonist (albuterol inhaled)

Enhanced Elimination
 Kayexalate (sodium polystyrene sulfonate) ion exchange resin
 Loop diuretic
 Hemodialysis
              Hypokalemia
              Plasma [K+] < 3.5
Hypokalemia may also result from disturbances
in external balance (total body K+ deficiency) or
internal balance (transmembrane K+ shifts)
  Hypokalemia: Disorders of External Balance




                  Increased          Increased
 Inadequate                       renal K+ losses
                  extrarenal
dietary intake                    + Hypertension
                  K+ losses



                                     Increased
                                  renal K+ losses
                                  - Hypertension
Hypokalemia: Disorders of External Balance




     Inadequate K+ Intake
        Malnutrition

     Extrarenal Losses
        Gastrointestinal losses
          Diarrhea
          Enteric fistulas

        Cutaneous losses
          Burns
 Hypokalemia: Disorders of External Balance



Disorders Associated with Renal Potassium Losses

   Hypertensive Disorders
     Hyperreninemia
         Renin excess (renal artery stenosis, renin-secreting tumor)

     Primary hyperaldosteronism (Conn’s Syndrome)
         Mineralocorticoid excess (adrenal hyperplasia, tumor)

     Cushing’s syndrome
         Glucocorticoid excess (exogenous, pituitary, adrenal)

     Congenital adrenal hyperplasia
         Enzymatic defects in cortisol biosynthesis (excess
          aldosterone precursors)
             Hypokalemia:
      Disorders of External Balance


Disorders Associated with Renal Potassium Losses

   Normotensive Disorders
     Diuretics
     Osmotic diuresis
         Glucosuria

     Renal tubular acidoses
     Prolonged vomiting, nasogastric drainage
     Ureteral diversion
         Ureteroileostomy, ureterosigmoidostomy
Hypokalemia: Disorders of Internal Balance




        Insulin excess
        Catecholamine excess
            Myocardial ischemia/infarction
            Delirium tremens
            Pharmacologic agents

        Alkalemia
        Cell proliferation
            Rapidly proliferating leukemia or lymphoma
     Clinical Manifestations of Hypokalemia




Cardiac               Metabolic
 EKG changes           Glucose intolerance
 Arrhythmias           Growth retardation

Smooth muscle         Renal
 Hypertension          Increased renal ammoniagenesis
 Ileus                 Nephrogenic diabetes insipidus

Skeletal muscle

 Weakness
 Rhabdomyolysis
            EKG Manifestations of Hypokalemia




                             Normal
Decreasing Serum K+



                             Flat T-wave


                             Prominent U-wave


                             Depressed ST-segment
Treatment of Hypokalemia




Potassium Replacement
  Oral or IV

Potassium-sparing diuretics
  ENaC sodium channel inhibitors
     Amiloride, triamterene
  Mineralocorticoid antagonists
     Spironolactone

				
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