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 Potassium BUN 144 4.4

5 Chloride CO 2 Creat Glucose 92 Osm 106 29 0.6

312

Polyuria

 Urine output exceeding 3 L per day  Etiology » Water diuresis – diabetes insipidus  central  nephrogenic – primary polydipsia » Solute diuresis

Evaluation of Polyuria

< 250 mosm/kg Water Diuresis Urine Osmolality 300-400 mosm/kg 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 dDAVP 5 u sc 4 6 8 TimeWt.

(hr) (lb) 0 2 234 232 BP (mmHg) Sosm Uosm (mosm/kg) 120/80 305 115/70 313 230 118/60 325 227 110/80 323 227 118/70 305 87 113 125 138 655

Regulation of ADH Release

P osm Effective Circulating Volume Thirst Water Intake Water Retention P osm Effective Circulating Volume ADH Water Excretion Figure 5

Sensitivities of Osmo- and Baroreceptor Regulation of ADH Release

20 Pressure Volume Basal Osmolality 15 10 5 0 -30 -15 0 Percent Change +15 Figure 6 +30

Effects of Hemodynamic Variables on the Osmo-regulation of ADH Release

10 Hypovolemia or Hypotension Hypervolemia or Hypertension 5 0 260 -20 -15 -10 N +10 +15 +20 300 Plasma Osmolality (mOsm/kg) Figure 7 340

Figure 3

Regulation of ADH Release

Angiotensin SFO PVN OVLT SON OC Osmolality ADH Pituiatry VLM Baroreceptors

Central DI

 Deficient secretion of ADH  Sudden onset of polyuria  Serum sodium tends to be > 142 mEq/L

5 4 3 2 1

Triphasic Changes in Water Balance after Hypothalmic Surgery

DI SIADH ADH release from degenerating posterior pituitary DI Hypothalamic Dysfunction 0 Urine Output (L/day) 2 4 6 8 10 Post-operative Day 12 14 16

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 Potassium 144 3.8

BUN 14 Chloride CO 2 Creat Glucose 98 Osm 100 24 1.5

292

Case Presentation 2 Cont’d

Water Deprivation Test dDAVP 5 u sc 4 6 8 TimeWt.

(hr) (lb) 0 2 196 195 BP (mmHg) Sosm Uosm (mosm/kg) 148/80 292 145/85 312 194.5 145/80 321 194 140/80 322 193 138/70 324 115 170 225 235 255

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 Spontaneous P osm > 295 Spontaneous P Na+ > 143 U osm > 500 U/P osm < 1.5

Primary Polydipsia dDAVP 5 mcg sc U osm Rises > 150 mosm/kg U osm < 300 mosm/kg Central DI Nephrogenic DI

ADH and Plasma Osmolality in Central DI with 5% Saline Infusion

10 Normal 5 Central DI 0 280 P osm 295 (mmol/kg) 310

ADH and Urine Osmolality in Nephrogenic DI with 5% Saline Infusion

1000 500 0 Normal Nephrogenic DI 0 5 10 Plasma ADH (pg/ml)

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

Tubular Lumen Aquaporin-2 H 2 O PKC PKA cAMP H 2 O ADH V 2 Receptor Aquaporins-3 and 4 H 2 O Hypertonic Medulla 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 Output

8 6 Solute intake (mosm/day) 900 4 2 0 100 110 120 130 Urine Osmolarity (mosm/kg) 140 600 300

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 Potassium BUN 141 4 10 Chloride CO 2 Creat 104 26 0.8

Glucose 77 Osm 288

Case Presentation 3 Cont’d

Water Deprivation Test Time Wt.

(hr) 0 1 2 3 4 (lb) 118 118 BP (mmHg) 98/65 U Vol.

(L) 110/60 .15

.1

Sosm Uosm ADH (mosm/kg) (pg/ml) 285 288 335 450 < 2.5

117 102/60 .125 289 550 117.5 102/70 .075 290 580 117.25 112/70 .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 -20 o C » Extract in acetone and petrol-ether » Freeze at -80 o C » Dessicate and store at -20 o C

Mechanisms of Thirst Regulation

1. Cerebral cortex Nonessential drinking Thirst 3. Hypothalamic Osmoreceptors 2. Oropharnygeal mechanoreceptors Stimulated by im bibing large volumes of water

Osmotic Regulation of Thirst and ADH Release

Thirst 6 3 0 275 280 285 290 Plasma Osmolality (mosm/kg) 295

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 Water Deprivation 800 dDAVP 600 400 200 280 285 290 295 P osm (mosm/kg) Normal Primary polydipsia Central DI Nephrogenic DI 300

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 Potassium BUN 168 3.6

5 Chloride CO 2 Creat 133 21 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 Potassium 170 3.9

BUN 8 Glucose 85 Chloride CO 2 Creat Osm 128 29 0.8

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