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Dysnatremias
Case Presentation 1
19 year old female with a history of depression is referred for polyuria and polydipsia. Over the past 2 years she developed polydipsia rather abruptly, frequently drinking 5 gallons of water per day. Medications included fluoxetine 20 mg daily and famotidine 20 mg daily.
Case Presentation 1 Cont’d
Physical Exam Obese, depressed affect
BP 126/80 HR 100
Trace edema
24 hr urine volume 13 liters
Urine osm 80 mosm/kg
Serum Sodium 144 Chloride 106
Potassium 4.4 CO2 29
BUN 5 Creat 0.6
Glucose 92 Osm 312
Polyuria
Urine output exceeding 3 L per day Etiology
» Water diuresis– diabetes insipidus
central nephrogenic
– primary polydipsia
» Solute diuresis
Evaluation of Polyuria
Urine Osmolality
< 250 mosm/kg 300-400 mosm/kg
Water Diuresis Solute Diuresis
Water Restriction Test
No intake 2-3 hours prior to test Measure:
» Hourly BP and weight» Hourly urine volume and osmolality» Plasma sodium and osmolality every 2 hour
Give dDAVP 5 mcg sc if no change in urine osm despite rising serum osm or if plasma osm > 295 mosm/kg
Case Presentation 1 Cont’d
Water Deprivation Test
TimeWt. BP Sosm Uosm
(hr) (lb) (mmHg) (mosm/kg)
0 234 120/80 305 87
2 232 115/70 313 113
4 230 118/60 325 125
6 227 110/80 323 138
8 227 118/70 305 655dDAVP 5 u sc
Regulation of ADH Release
Posm
Effective Circulating Volume
Thirst
Water Intake
ADH
Water Excretion
Water Retention
Posm
Effective Circulating Volume
Figure 5
Sensitivities of Osmo- and Baroreceptor Regulation of ADH
Release
0 +15 +30-15-30
20
10
15
5
0
BasalOsmolalityVolume
Pressure
Percent Change
Pla
sma
Vas
opre
ssin
(pg
/mL)
Figure 6
Effects of Hemodynamic Variables on the Osmo-
regulation of ADH Release
5
10
0Pla
sma
Vas
opre
ssin
(pg
/ml)
Plasma Osmolality (mOsm/kg)340300260
-15
+20+15
+10N
-10-20
Hypovolemia orHypotension
Hypervolemia orHypertension
Figure 7
Regulation of ADH Release
SFO
OVLT
OC
SON
PVN
PituiatryOsmolality
Angiotensin
VLM
BaroreceptorsADH
Figure 3
Central DI
Deficient secretion of ADH
Sudden onset of polyuria
Serum sodium tends to be > 142 mEq/L
Triphasic Changes in Water Balance after Hypothalmic Surgery
0 2 4 6 8 10 12 14 16
1
2
3
4
5
UrineOutput(L/day)
Post-operative Day
HypothalamicDysfunction
ADH releasefrom degeneratingposterior pituitary
DI SIADH DI
Causes of Central DI
Idiopathic Familial Neurosurgery or trauma Malignancy Hypoxic encephalopathy Sheehan’s syndrome Infiltrative disorders
Treatment of Central DI
dDAVP» Nasal spray 5-20 mcg every 12-24 hours» Tablet 0.1-1.2 mg daily» Follow serum Na+ and urine volume
Chlorpropamide 125-250 mg daily Carbamezepine 100-300 mg BID Clofibrate 500 mg QID Thiazide diuretics NSAIDs
Case Presentation 2
39 y.o. female with a history of schizo-phrenia and bipolar disorder is referred for polyuria and polydipsia. Found to be drinking out of bathtub and commode. Had been treated with lithium in the past (>1 year ago).
Case Presentation 2 Cont’d
Physical Exam BP 156/80 HR 92
Trace edema
24 hr urine volume 6000 ml
Urine osm 68 mosm/kg
Serum Sodium 144 Chloride 100
Potassium 3.8 CO2 24
BUN 14 Creat 1.5
Glucose 98 Osm 292
Case Presentation 2 Cont’d
Water Deprivation Test
TimeWt. BP Sosm Uosm
(hr) (lb) (mmHg) (mosm/kg)
0 196 148/80 292 115
2 195 145/85 312 170
4 194.5 145/80 321 225
6 194 140/80 322 235
8 193 138/70 324 255dDAVP 5 u sc
Factors Complicating the Diagnosis of DI
Medullary washout
Central DI is often partial
Decrement in ADH activity in nephrogenic DI is often partial
Elevated residual bladder capacity
Indirect Testing
Water Deprivation Test
Uosm > 500 U/Posm < 1.5
dDAVP 5 mcg sc
Uosm Rises > 150 mosm/kg
Central DI
Uosm < 300 mosm/kg
Nephrogenic DI
Spontaneous Posm > 295 Spontaneous PNa+ > 143
Primary Polydipsia
ADH and Plasma Osmolality in Central DI with 5% Saline
Infusion
Posm (mmol/kg)
Pla
sma
AD
H (
pg/m
l)
0
5
10
280 295 310
Normal
Central DI
ADH and Urine Osmolality in Nephrogenic DI with 5% Saline
Infusion
Plasma ADH (pg/ml)
Urin
e O
smol
ality
(m
osm
/kg)
0
500
1000
0 5 10
Nephrogenic DI
Normal
Nephrogenic DI
Normal ADH secretion, but renal resistance to ADH activity
Gradual onset
Serum sodium tends to be > 142 mEq/L
Effect of ADH on Principle Cells in the Collecting
Ducts
ADH
cAMP
Tubular Lumen
PKAPKCAquaporin-2
Aquaporins-3 and 4H2O
H2O H2O
Hypertonic Medulla
V2 Receptor
Figure 4
Causes of Nephrogenic DI
Hereditary X-linked V2 receptor defect Hereditary AR Aquaporin-2 defect Lithium toxicity Hypercalcemia Hypokalemia Cidofovir and Foscarnet Advanced age Renal failure
Aquaporin-2 Excretion
Aquaporin-2 excretion is several-fold higher in normals compared with those with central DI
Aquaporin-2 excretion increases with exogenous ADH in patients with central DI and not in patients with nephrogenic DI
Treatment of Nephrogenic DI
Diuretics» thiazides» amiloride (lithium)
Low salt, low protein diet NSAIDS
» prostaglandins normally antagonize ADH activity
dDAVP
Relationship Between Solute Intake and Urine
OutputW
ater
Cle
aran
ce (
L/da
y)
0
2
4
6
8
100 110 120 130 140Urine Osmolarity (mosm/kg)
Solute intake(mosm/day)
900
600
300
Case Presentation 3
47 year old female referred for polyuria. She initially presented to her urologist for urinary incontinence. A bladder neck suspension was performed, and the patient was subsequently found to have large post-void residuals of 300-400 ml. She denied nocturia, history of head trauma, and was on no medications.
Case Presentation 3 Cont’d
Physical Exam Normal blood pressure and pulse. No edema.
24 hr urine volume 5000 ml
Urine osm 178 mosm/kg
Serum Sodium 141 Chloride 104
Potassium 4 CO2 26
BUN 10 Creat 0.8
Glucose 77 Osm 288
Case Presentation 3 Cont’d
Water Deprivation Test
Time Wt. BP UVol. Sosm Uosm ADH
(hr) (lb) (mmHg) (L) (mosm/kg) (pg/ml)
0 118 110/60 .15 285 335 < 2.5
1 118 98/65 .1 288 450
2 117 102/60 .125 289 550
3 117.5 102/70 .075 290 580
4 117.25 112/70 .1 297 600 < 2.5
Radioimmunoassay of ADH
Assay is cumbersome High incidence of falsely low values Sample preparation
» Collect in chilled 7 ml EDTA tubes» Centrifuge 1000 g X 20 min» Freeze at -20oC» Extract in acetone and petrol-ether» Freeze at -80oC» Dessicate and store at -20oC
Mechanisms of Thirst Regulation
1. Cerebral cortex Nonessential drinking
2. Oropharnygeal mechanoreceptors Stimulated by im- bibing large volumes of water
3. Hypothalamic Osmoreceptors
Thirst
Osmotic Regulation of Thirst and ADH Release
0
3
6
Pla
sma
AD
H (
pg/m
l)
295290285280275Plasma Osmolality (mosm/kg)
Thirst
Primary Polydipsia
Central defect in thirst regulation» osmotic threshold thirst < ADH» continue to drink until the plasma osm is
less than the threshold Neuroleptic therapy
Treatment of Primary Polydipsia
Clozapine may correct the central disturbance in thirst regulation
Limit use of drugs that cause dry mouth
ACE inhibitors
Urine and Plasma Osmolality in Disorders of
Water Balance
1000
800
600
400
200
280 285 290 295 300Posm(mosm/kg)
Uo
sm(m
osm
/kg)
Normal
Primary polydipsia
Central DI
Nephrogenic DI
WaterDeprivation dDAVP
Case Presentation 4
29 y.o. female with a 31 week intrauterine pregnancy admitted with a 2 week history of polyuria and polydipsia. She reported 6-8 liters of daily fluid intake and voided urine every 30 minutes to an hour.
Case Presentation 4 Cont’d
Physical exam BP 130/80, HR 150, trace pretibial edema
24 hr urine volume 7000 ml
Urine osm 162 mosm/kg
Serum Sodium 168 Chloride 133
Potassium 3.6 CO2 21
BUN 5 Creat 2.8
Glucose 77 Osm 348
Polyuria in Pregnancy
Vasopressinases are released from the placenta resulting in a four-fold rise in ADH catabolism» May be treated with dDAVP which is
resistant to vasopressinase» Polyuria often seen in patients with
decreased ADH secretory reserve Central DI in Sheehan’s syndrome
Case Presentation 5
A 16 y.o. male was treated for the “flu” at home. Despite improvement in his fever and cough, worsening lethargy prompted his mother to bring him to the E.R.
Physical Exam
Afebrile BP 140/85 no edema
Disoriented No focal neurologic deficits
Case Presentation 5 Cont’d
Laboratory data
24 hr urine volume 4000 ml
Urine osm 400 mosm/kg
Serum Sodium 170 Chloride 128
Potassium 3.9 CO2 29
BUN 8 Creat 0.8
Glucose 85 Osm 360
Solute (Osmotic) Diuresis
Etiology» Glucose» High-protein feedings (urea)» Expanded ECF volume» Release of urinary tract obstruction
Urine osm > 300 mosm/kg Osmolar excretion > 900 mosm per day
Postobstructive Diuresis
Urine output after release of obstruction may initially exceed 500-1000 ml/hr
This solute diuresis is appropriate Administer normal replacement fluids
(e.g. 1/2 NS at 75 ml/hr) Replacing fluids at a rate greater than
replacement level will only exacerbate the solute diuresis