Case Study 1
A 14-year-old male with a history of aplastic anemia underwent haploidentical stem cell transplantation, complicated by graft-versus-host disease, affecting his gastrointestinal tract. The posttransplantation course was complicated by bacteremia caused by Klebsiella species and subsequently fungal sinusitis, requiring sphenoidectomy and an extended course of antifungal therapy. One month later, nephrology was consulted for polyuria. The patient denied headache, confusion, changes in vision, weakness, or difficulty ambulating. His medications were limited to amlodipine, amphotericin B, budesonide, omeprazole, posaconazole, and terbinafine. He was receiving total parenteral nutrition and 3 L of lactated Ringer’s solution daily before consultation.
On physical examination, vital signs were notable for temperature of 36.8°C, heart rate 87 beats/min, blood pressure 131/86 mmHg, respiration rate 14 breaths/min, and oxygen saturation 98% on room air. Weight was 80.5 kg. Cardiac examination findings were unremarkable, lungs were clear bilaterally, abdomen was soft without tenderness or organomegaly, extremities were without pitting edema, and there were no focal neurologic findings. The patient’s urine output was 6.8 L daily. Laboratory data included serum sodium 155 mmol/L, potassium 3.4 mmol/L, chloride 115 mmol/L, bicarbonate 28 mmol/L, BUN 28 mg/dL, creatinine 1.4 mg/dL. Urine sodium was 42 mmol/L, potassium 10 mmol/L, and osmolality 155 mOsm/kg. Magnetic resonance imaging of the brain revealed stable mucosal thickening and enhancement within the sphenoid sinus, compatible with fungal sinusitis.
What is the diagnostic approach to polyuria?
- A.
Nephrogenic diabetes insipidus
- B.
Primary polydipsia
- C.
Central diabetes insipidus secondary to invasive fungal sinusitis
- D.
Reset hypernatremia
The correct answer is C
Comment: Polyuria, defined as 24-hour urine volume ≥ 3 L in patients consuming a typical Western diet, can be secondary to either solute or water diuresis. The initial diagnostic step is to measure urine osmolality. Levels greater than 300 mOsm/kg are suggestive of an osmotic diuresis or renal concentrating defect (if solute excretion rate is < 1000 mOsm/day). Urine osmolality less than 250 mOsml/kg is suggestive of water diuresis, which can be further stratified by assessing plasma sodium concentration. A level less than 136 mEq/L suggests primary polydipsia, whereas water diuresis that persists at a plasma sodium level greater than 140 mEq/L is consistent with a diagnosis of diabetes insipidus.
In hospitalized patients, polyuria is typically secondary to iatrogenic administration of large amounts of crystalloid or high-protein enteral nutrition. 1 Alternatively, excessive urine output may be seen following relief of urinary tract obstruction, due to a reduction in the medullary concentration gradient and impaired sodium reabsorption. At the time of consultation, the urine osmolality of 380 mOsm/kg and daily solute excretion (urine osmolality multiplied by 24-hour urine volume) were significantly greater than 1000 mOsm/day, both consistent with solute diuresis. The most likely cause was iatrogenic, secondary to crystalloid infusion. After discontinuation of intravenous fluids, the patient’s urine output improved to 2 L daily.
What treatment options would you consider in the short and long term?
- A.
Free-water 4.5 L
- B.
0.45% saline 3.0 L
- C.
0.9% saline 1.5 L
- D.
Ringer lactate 2.0 L
The correct answer is A
Comment: Given the free-water deficit of 4.5 L [V × (1 − (U Na + + U K )/P Na + )], the patient was started on an infusion of dextrose 5% in water solution at a rate of 300 mL/h in addition to receiving desmopressin, as described. Serum sodium level improved from 155 to 144 mEq/L during the subsequent 12 hours. He was successfully maintained on oral desmopressin treatment at a dosage of 0.1 μg daily.
Case Study 2
A 15-year-old male with a history of hypertension, hepatitis C virus infection previously treated with ledipasvir/sofosbuvir, and cirrhosis presented to an outside hospital with jaundice. His cirrhosis had been complicated by encephalopathy. He was found to have stigmata of advanced liver disease, including marked ascites and peripheral edema. Computed tomography showed a mass obstructing the biliary tree, and a biliary drain was placed. The patient’s serum sodium level during this admission was 135 mmol/L and ranged from 135 to 137 mmol/L until placement of the biliary drain, after which sodium level decreased to 129 mmol/L at discharge. Before this, he had no history of hyponatremia. The hyponatremia was attributed to treatment with a thiazide diuretic that was discontinued. He was discharged with plans for further workup of the mass as an outpatient. One week later, the patient presented to the Emergency Department with persistent jaundice and was found to have a serum sodium concentration of 122 mmol/L. His presenting laboratory values were notable for serum creatinine level of 1.96 mg/dL, serum osmolarity of 272 mOsm/kg in the setting of azotemia (serum urea nitrogen, 66 mg/dL), and serum glucose level of 150 mg/dL. Total bilirubin level was elevated at 15.6 mg/dL and albumin level was 3.6 g/dL. He estimated his daily fluid intake at about 7 L. Heart rate was 73 beats/min, blood pressure was 113/62 mmHg, and oxygen saturation was 98% while breathing room air. Physical examination revealed dry mucous membranes, no jugular venous distension, no cardiac murmur, clear lung fields, a large pannus with right upper quadrant biliary drain, but no fluid wave, and edema (1 +) of the lower extremities. His laboratory data: serum sodium 122 mmol/L, potassium 4.2 mmol/L, chloride 87 mmol/L, glucose 150 mg/dL, osmolality 282 mOsm/kg, and uric acid 9.9 mg/dL, Random urine chemistry showed sodium 7 mmol/L, potassium 39 mmol/L, and osmolality 443 mOsm/kg. Daily fluid intake and urine output averaged 1070 mL and 4200 mL, respectively.
The patient was initially thought to have hypervolemic, hypotonic hyponatremia secondary to cirrhosis and treated with furosemide and fluid restriction. His biliary drain produced 2 to 3 L/day. Serum sodium level continued to decline, including after administration of 500 mL of lactated Ringer’s solution. Hypertonic saline (3.0%) solution was administered at a rate of 115 mL/h with transient improvement in serum sodium concentration, but hyponatremia quickly recurred when this was discontinued.
What is the cause of hyponatremia in this patient and what additional diagnostic study should be obtained?
- A.
Hypovolemic, hypotonic hyponatremia from intravascular volume depletion secondary to excessive biliary output of high sodium content
- B.
Hyponatremia secondary to syndrome of inappropriate antidiuretic secretion (SIADH)
- C.
Hyponatremia secondary to polydipsia
- D.
Hyponatremia secondary to use of diuretics
The correct answer is A
Comment: The differential diagnosis of hyponatremia in this patient includes hypervolemic hyponatremia, hypovolemic hyponatremia, pseudohyponatremia secondary to lipoprotein X, and syndrome of inappropriate antidiuretic hormone (SIADH). Patients with obstructive jaundice accompanied by extreme elevations of serum cholesterol levels can have elevation of lipoprotein X levels from the reflux of unesterified cholesterol and phospholipids into the circulation. This can decrease the measured serum sodium level without affecting tonicity, which would be noted clinically by serum osmolality in the normal range. This is rare, and our patient was found to be hypotonic, with serum osmolality consistent with his serum sodium concentration. The presence of ascites and edema was indicative of a total-body excess of sodium and water and hypervolemic hyponatremia. A low urinary sodium concentration in such patients is common, reflecting decreased effective arterial blood volume despite the hypervolemic state due to systemic vasodilatation and splanchnic sequestration of fluid resulting in “third spacing” with the formation of ascites and edema. A hemodynamic impetus for antidiuretic hormone (ADH) release occurs, resulting in concentrated urine and hyponatremia. Although SIADH is a possibility, the diagnosis cannot be made in the face of signs of intravascular volume depletion as is seen in this patient, given his very low urinary sodium level. In SIADH, there is a slightly volume-expanded state; thus, this entity should not have a sodium-avid nephron as in intravascular volume depletion.
The observed failure to sustain a response to hypertonic saline solution infusions suggested ongoing sodium chloride losses with substantial water intake. Sequestration of sodium in bile salts is responsible for bile’s hypertonicity. Other studies have shown electrolyte excretion into bile to be related to the flow and presence of cholelithiasis. It should be noted that most fluids, including gastric and duodenal secretions, are hypotonic to serum; however, biliary secretions are hypertonic, whereas pleural fluid, ascites, and edema are isotonic. (Diarrhea has variable tonicity.) In this patient, the high urinary osmolality indicated the presence of ADH while the low urinary sodium concentration indicated that the kidneys were in a sodium-avid state, making it likely that the stimulus for ADH secretion was hemodynamic in response to intravascular volume depletion. The continued sodium losses from his biliary drain compounded with persistent fluid intake resulted in persistent ADH stimulus and hyponatremia.
Case Study 3
This 3-year-old girl was seen in the outpatient clinic with a 2-week history of anorexia, fatigue, polydipsia, and excessive polyuria. The fluid intake had risen to 0.5 L/h, and a 24-hour urine collection yielded 10 L. Her blood pressure at home was 106/64 mmHg with a pulse of 72 beats/min, and she complained of muscle cramps. Physical examination showed a euvolemic patient in an otherwise normal condition. Laboratory investigation revealed serum sodium 144 mmol/L, potassium 3.1 mmol/L, chloride 109 mmol/L, bicarbonate 29 mmol/L, and creatinine 0.3 mg/dL. Plasma osmolality of 298 mOsm/kg and urine osmolality of 44 mOsm/kg. Random urine sodium was 5 mmol/L and potassium 3 mmol/L.
What is the MOST likely Diagnosis?
- A.
X-linked type of nephrogenic diabetes insipidus
- B.
Hypokalemia-related polyuria
- C.
Recessive type of nephrogenic diabetes insipidus
- D.
Solute induced polyuria
The correct diagnosis is C
Comment: Constellation of polydipsia and polyuria (10 L/day), elevated serum sodium (144 mmol/L), and dilute urine (urine osmolality 44 mOsml/kg) in a setting of normal blood pressure suggests the diagnosis of autosomal recessive hereditary, nephrogenic diabetes insipidus.
In this patient, nephrogenic diabetes insipidus was caused by a homozygote mutation in the aquaporin-2 gene due to consanguine marriage. The patient’s brother died at the age of 14 days, and her sister died at the age of 4 months. Aquaporin-2 channels are normally stored in the cytosol; under the influence of antidiuretic hormone, they move to and fuse with the luminal membrane, thereby allowing water to be reabsorbed down the favorable concentration gradient. The mutations may lead either to impaired trafficking of the water channels, which do not fuse with the luminal membrane, or to decreased channel function. The patient was taking amiloride-hydrochlorothiazide (Moduretic) twice daily, a combination of hydrochlorothiazide (50 mg) with amiloride hydrochloride (5 mg). The thiazide diuretic acts by inducing mild volume depletion with an increase of proximal sodium and water reabsorption, thereby diminishing water delivery to the antidiuretic hormone-sensitive sites in the collecting tubules and reducing the urine output. This initial natriuresis can be enhanced by a combination therapy with amiloride.
Current conventional treatment regimen includes hydration, diuretics polyuria. Recent experimental studies have suggested that treatment with sildenafil, a selective phosphodiesterase inhibitor, may enhance cyclic guanosine monophosphate (cGMP) mediated apical trafficking of AQP2 and may be effective in increasing water reabsorption in patients with congenital nephrotic syndrome.
Case Study 4
A 19-year-old male is brought into the hospital in a comatose state. He is found to have a skull fracture. It is noted that his weight is 70 kg, and his urine output is 175 mL/h. The following laboratory data are obtained: Serum sodium 168 mmol/L, potassium 4 mmol/L, chloride 130 mmol/L, bicarbonate 25 mmol/L, plasma osmolality 350 mOsm/kg, and urine osmolality 80 mOsm/kg.
What is the MOST likely diagnosis, what is the approximate water deficit and much free water is needed to lower the plasma sodium concentration to normal (assuming that the urine output has fallen to low levels)?
- A.
Nephrogenic diabetes insipidus
- B.
Central diabetes insipidus
- C.
Syndrome inappropriate ADH secretion
- D.
Essential hypernatremia
The correct answer is B
Comment: The diagnosis of central diabetes insipidus was confirmed by the good response to administration of 1-deamino-8- d -arginine vasopressin (dDAVP) or aqueous vasopressin, which raised the urine osmolality and lowered the urine volume. There was no need to do the water-restriction test since the plasma osmolality was already 350 mOsml/kg.
The water deficit can be estimated from:
Water deficit=0.5×70×(168/140−1)or7L
This deficit should be replaced gradually over 56 hours at the rate of 125 mL/h. Another 50 mL/h should be added to replace continuing insensible losses. Thus, 175 mL/h can be given as dextrose in water. There is no history of sodium loss and therefore no requirement for saline administration.
Case Study 5
A 10-year-old girl presents to hospital after 2 days history of vomiting and diarrhea. She appears moderately dehydrated on exam. Her temperature is 39°C, weight 25 kg, blood pressure 110/62 mmHg, pulse 90 beats/min, and respiration 18 breaths/min. Her weight was 27 kg prior to her illness. The serum sodium concentration is 160 mmol/L and potassium 3.4 mmol/L.
What solution should be used and at what rate to correct this patient’s hypernatremia?
- A.
0.45% saline at 200 mL/h
- B.
0.9% saline at 200 mL/h
- C.
0.3% saline at 100 mL/h
- D.
0.2% saline at 300 mL/h
The correct answer is A
Comment: This patient’s hypovolemic hypernatremia is as a result of hypotonic sodium loss from gastrointestinal tract. She has lost both sodium and water. However, the amount of water loss is greater than sodium loss and that’s why she is hypernatremic. Infusion of hypotonic fluids (such as 0.45% saline) is the most appropriate solution to correct volume depletion and reduce serum sodium concentration.
The effect of 1 L of 0.45% saline containing 20 mmol KCl/L on serum sodium change can be estimated using the following formula :
Na+change=(infusate(Na+mmo/L+infusateK+mmo/L))−(serumNa+mEq/L)÷(total body water (TBW) liters+1)
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