RENAL FUNCTION by sofiaie

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									          WATER METABOLISM




                       INTAKE      OUTPUT



Unregulated: food & social drink    Insensible and obligate loss

Regulated:    thirst                AVP modulated water output
THIRST


   Hyperosmolar stimulus
      hypothalamic osmoreceptors

      threshold 1 to 4% above basal




   Hypovolaemic stimulus
      baroreceptors

      threshold 10 - 15%

      ? absent in man (inconvenient with postural change!)




   Normally inactive as unregulated input is in excess
                      10                                         100




                                                                       Subjective thirst (analogue scale)
                      8                 BASAL
Plasma AVP (pmol/L)




                      6


                      4


                      2


                      0                                           0
                       270      280       290        300       310
                             Plasm a osm olality (m Osm /Kg)
AVP secretion


   Synthesized in hypothalamic SON and PVN nuclei

   Stored and released from posterior pituitary (> 1 week store!)

   Interacts via V2 receptors to insert aquaporin-2 water channels

   Osmolar threshold within ‘normal range’

   High ‘gain’ (i.e steep curve and high renal sensitivity)
AVP secretion



   Osmotic stimulus        high sensitivity

   Hypovolaemic stimulus   high threshold (>10%)
AVP secretion



   Osmotic stimulus        high sensitivity

   Hypovolaemic stimulus   high threshold (>10%)

   Nausea                  most powerful known

   Stress                  e.g. post-operative

   Drugs                   ‘SIADH’
INTEGRATION OF THIRST AND AVP



   Unregulated water intake supplies water in excess of need

   Excess water is excreted

   AVP secretion regulates free water clearance

   AVP maintains osmolality within narrow limits

   This avoids ‘inconvenient’ thirst and water-seeking behaviour

   Thirst kicks-in when deficiency reaches harmful levels
          DIFFERENTIAL DIAGNOSIS OF HYPONATRAEMIA
                                        HYPONATRAEMIA


Pseudo-             YES
                                     Lipaemia / hyperproteinaemia ?
hyponatraemia
                                                     NO

Compensatory        YES
                                           Hyperglycaemia ?
hyponatraemia
                                                     NO

                Volume                                                               Volume
                                            Total body water
                depleted                                                            expanded


        Renal          Extra-renal                                    No oedema                 Oedema
        loss              loss



      Diuretics        Vomiting                                 SIADH                          Nephrotic
      Addison’s        Diarrhoea                                Hypothyroid                    Cirrhosis
                                                                                               CCF
UNa     >20                <10                                          >20                       <10

Rx         Normal saline                                                      Fluid restriction
                Causes of hyponatraemia
                                        HYPONATRAEMIA


Pseudo-             YES
                                     Lipaemia / hyperproteinaemia ?
hyponatraemia
                                                     NO

Compensatory        YES
                                           Hyperglycaemia ?
hyponatraemia
                                                     NO

                Volume                                                               Volume


                           HYPO-OSMOLAL
                                            Total body water
                depleted                                                            expanded


        Renal          Extra-renal                                    No oedema                 Oedema
        loss              loss




                           > 95% OF CASES
      Diuretics        Vomiting                                 SIADH                          Nephrotic
      Addison’s        Diarrhoea                                Hypothyroid                    Cirrhosis
                                                                                               CCF
UNa     >20                <10                                          >20                       <10

Rx         Normal saline                                                      Fluid restriction
                Causes of hyponatraemia
                                        HYPONATRAEMIA


Pseudo-             YES
                                     Lipaemia / hyperproteinaemia ?
hyponatraemia
                                                     NO

Compensatory        YES
                                           Hyperglycaemia ?
hyponatraemia
                                                     NO

                Volume                                                               Volume
                                            Total body water
                depleted                                                            expanded


        Renal          Extra-renal                                    No oedema                 Oedema
        loss              loss



      Diuretics        Vomiting                                 SIADH                          Nephrotic
      Addison’s        Diarrhoea                                Hypothyroid                    Cirrhosis
                                                                                               CCF
UNa     >20                <10                                          >20                       <10

Rx         Normal saline                                                      Fluid restriction
    Case 1


   A 58-year old man presented with a history of general
    malaise and a persistant painful cough of three months
    duration

Serum
        Sodium          116    mmol/L
        Potassium       3.4    mmol/L
        Urea            9.4    mmol/L

        Bilirubin       12     umol/L
        Alk phos        95     U/L
        ALT             23     U/L
        Albumin         20     g/L
        Total protein   120    g/L
                Causes of hyponatraemia
                                        HYPONATRAEMIA


Pseudo-             YES
                                     Lipaemia / hyperproteinaemia ?
hyponatraemia
                                                     NO

Compensatory        YES
                                           Hyperglycaemia ?
hyponatraemia
                                                     NO

                Volume                                                               Volume
                                            Total body water
                depleted                                                            expanded


        Renal          Extra-renal                                    No oedema                 Oedema
        loss              loss



      Diuretics        Vomiting                                 SIADH                          Nephrotic
      Addison’s        Diarrhoea                                Hypothyroid                    Cirrhosis
                                                                                               CCF
UNa     >20                <10                                          >20                       <10

Rx         Normal saline                                                      Fluid restriction
    Case 3



   A 66-year old man was admitted for investigation of possible
    bronchogenic carcinoma

    Serum                                     Ref range
        Sodium         121     mmol/L         133 – 143
        Potassium      4.1     mmol/L         3.6 – 4.6
        Urea           4.4     mmol/L         3.0 – 7.0
    Case 3



   A 66-year old man was admitted for investigation of possible
    bronchogenic carcinoma

    Serum                                     Ref range
        Sodium         121     mmol/L         133 – 143
        Potassium      4.1     mmol/L         3.6 – 4.6
        Urea           4.4     mmol/L         3.0 – 7.0
        Glucose        5.2     mmol/L
    Case 3



   A 66-year old man was admitted for investigation of possible
    bronchogenic carcinoma

    Serum                                     Ref range
        Sodium         121     mmol/L         133 – 143
        Potassium      4.1     mmol/L         3.6 – 4.6
        Urea           4.4     mmol/L         3.0 – 7.0
        Glucose        5.2     mmol/L

        Osmolality     250     mmol/Kg        275 - 295

    Urine
        Osmolality     614     mmol/Kg
SYNDROME OF INAPPROPRIATE ADH


   Hyponatraemia is very common

       up to15% hospitalised patients

       affects 50% of nursing home residents each year

       >30% acutely ill nursing home patients have hyponatramia



   SIADH accounts for about 50% of all chronic hyponatraemias
SYNDROME OF INAPPROPRIATE ADH


Bartter and Schwartz criteria (1967)

      hyponatraemia with hypotonicity of plasma

      urine osmolality inappropriately high

      ongoing renal sodium excretion

      absence of oedema or volume depletion

      normal renal and adrenal function



i.e. normovolaemic hyponatraemia
   SYNDROME OF INAPPROPRIATE ADH


     Symptoms relate to rate of fall as well as severity

       Sodium <120 mmol/L         Sodium <110 mmol/L
        Lethargy                  Drowsiness
        Anorexia                  Confusion
        Nausea and vomiting       Depressed reflexes
        Irritability              Extensor plantar responses
        Headache                  Seizures
        Muscle weaknes            Coma
        Cramps                    Death


No oedema because water distributed in both compartments
SIADH - pathogenesis



   Inappropriately high AVP levels

   Ongoing (unregulated) water intake

   Blood volume rises

   >10% expansion inhibits aldosterone and triggers natriuresis
       Causes of SIADH


Neoplasia              Lung disease     Neurological disorders
 Carcinoma of lung,    Pneumonia       Meningitis
  pancreas, bladder     TB              Encephalitis
 Leukaemia             Pneumothorax    Brain tumour
 Thymoma               Asthma          Subarachnoid haemorrhage
 Lymphoma              IPPV            Cerebral and cerebellar atrophy
 Sarcoma                                Guillain-Barré syndrome
 Mesothelioma                           Acute intermittent porphyria
                                         Shy-Drager syndrome
                                         Head injury
Causes of SIADH


   Drugs               Miscellaneous
    Vasopressin         Acute psychosis
    Oxytocin            Post-operative state
    Vinca alkaloids     AIDS
    Cisplatin           Glucocorticoid deficiency
    Chlorpropamide      Severe hypothyroidism
    Carbamazepine       Idiopathic
    Phenothiazines
    Thiazides
    MAOI’s
    SSRI’s
    Tricyclics
    Nicotine
    Ecstacy
The impact of ageing on water metabolism


   Rise in osmotic sensitivity of ADH release

   Delayed ability to excrete water load

   Thirst mechanism diminishes

   Decrease in maximal urinary concentrating ability

   Decreased renal mass

   Impaired responsiveness to sodium balance

   Multiple drug therapy

   A lifetime of accumulated disease and comorbidities
The impact of ageing on water metabolism


    Rise in osmotic sensitivity of ADH release
                                                 }

                                                     predispose
   Delayed ability to excrete water load            to SIADH

   Thirst mechanism diminishes

   Decrease in maximal urinary concentrating ability

   Decreased renal mass

   Impaired responsiveness to sodium balance

   Multiple drug therapy

   A lifetime of accumulated disease and comorbidities
Patterns of AVP release in SIADH
    Diagnosis of SIADH

   Essential criteria
        True plasma hypo-osmolality (<275 mOsm/Kg)
        Inappropriate urine osmolality (>~100 mOsm/Kg)
        Euvolaemia; no oedema, ascites or intravascular hypovolaemia
        Urine sodium not low (>30 mmol/L during normal intake)
        Normal renal, adrenal, and thyroid function


   Supplemental criteria
        Low serum urea and urate
        Unable to excrete >80% of water load (20mL/Kg) in 4h and/or failure
         to achieve urine osmolality <100 mOsm/Kg
        No significant rise in serum [Na] after volume expansion but
         improvement with fluid restriction
    Treatment of SIADH


   Identification and treatment of underlying cause


   Clearance of excess water
        not necessary in asymptomatic chronic hyponatraemia
        fluid restriction to 500 - 1000 mL/24h
        Demeclocycline
             600 to 1,200 mg daily
             may take three weeks to reach maximal effect
             caution in renal or hepatic insufficiency
        Specific V2 receptor antagonists (OPC-31260)
Treatment of SIADH

   Hypertonic saline
        Only if significantly symptomatic or duration <3 day
        Calculate sodium required


     Na+ req. (mmol) = (125 – [Na+]) x 0.6 x body weight (kg)


        Also measure and re-infuse urinary sodium output


        Rate of increase not usually >0.5 mmol/L/h


        ? combine with i.v. furosemide
        Stop saline when sodium reaches 120 - 125 mmol/L
         Treatment of SIADH
              Na+ req. (mmol) = (125 – [Na+]) x 0.6 x body weight (kg)


   Example: symptomatic patient with sodium 105 mmol/L
        Body weight 60 Kg
        Available hypertonic saline 2.7 % (3 normal)


             Sodium requirement = (125-105) x 0.6 x 60 = 720 mmol

             2.7% saline = Na+ 462 mmol/L

             Correction at 0.5 mmol/L/hr  correction over 25 hrs

             2.7% saline requirement 720/462 L = 1.56 L

             Infusion rate 1.56/25 = 62 mL/hr (plus extra for ongoing urinary Na+ output)
Other causes of euvolameic hyponatraemia


   Psychogenic hyponatraemia
        Massive water intake (20 - 30 L/day)
        Urine osmolality <100 mOsm/kg


   Beer-drinker’s potomania
        High volume low solute drinks impair ability to excrete water


   Hypothyroidism
        Reset osmostat


   Pure glucocorticoid deficiency
        Cortisol is required for renal free water excretion
     Cerebral salt wasting


SIADH                              CSW
  1º increase in AVP               Cerebral damage
  Inappropriate urine hyperosm.    Reduced SNS efferents +/- BNP
  Volume-expansion                 Inappropriate natriuresis
  Suppressed aldosterone           Volume-depletion
  Appropriate natriuresis          Volume mediated AVP release
  Decreased urea and urate         Appropriate urine hyperosm.

Treatment: fluid restriction       Treatment: Normal saline infusion
    Case 4

   A 53-year old bachelor was brought to the A&E department having
    been found semi-comatose. He was known to be a heavy drinker of
    alcohol. On examination he was jaundiced. His abdomen was
    distended; there was hepatomegaly and evidence of ascites. He
    had ankle oedema.

    Serum                                        Ref range
         Creatinine      84      µmol/L          75 – 120
         Urea            10.0    mmol/L          3.0 – 7.0
         Sodium          111     mmol/L          133 – 143
         Potassium       4.9     mmol/L          3.6 – 4.6

         Bilirubin       166     µmol/L          < 17
         Alk phos        175     U/L             21 - 92
         ALT             450     U/L             5 – 40
         Albumin         24      g/L             35 – 55
         Total protein   72      g/L             62 – 80
         Globulin        48      g/L             22 - 36
       Oedematous hyponatraemia

              Splanchnic arterial underfilling / vasodilatation

                                     
                       Non-osmotic release of AVP

                                     
Reduced               Impaired renal water retention              Impaired PG
delivery of
                                                                  synthesis
filtrate                             
                       Dilutional hyponatraemia

								
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