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