Solution to "A 42-Year-Old Man With HIV"

Robert M. Centor, MD

Disclosures

December 12, 2006

This is the solution to a case we presented recently. The patient was a 42-year-old man with known HIV infection, admitted with headache and a fever. The physicians diagnosed cryptococcal meningitis and started amphotericin B and 5-fluorocytosine (5-FC). One week later, on rounds, the patient was found to be confused.

These were the patient's lab values:

Electrolyte panel: Sodium 152 mEq/L; potassium 3.4 152 mEq/L; chloride 120 152 mEq/L; bicarbonate 20 152 mEq/L; blood urea nitrogen (BUN) 32; creatinine 1.4 mg/dL; glucose 112 mg/dL

Arterial blood gas: pH 7.30; pCO2 36; pO2 85

Plasma osmolality 315 mOsm/kg; urine osmolality 150 mOsm/kg; urine Na+ 25 mEq/L; urine K+ 45mEq/L; urine Cl- 38mEq/L; urine pH 6.2

First, note that despite his hypernatremia, the patient has dilute urine (Osm 150). In hypernatremia, we expect the kidneys to concentrate the urine. Thus, he must be unable to concentrate the urine. We conclude that he has central diabetes insipidus; a lack of antidiuretic hormone (ADH) is a known complication of cryptococcal meningitis.

Second, the patient also has a normal gap acidosis. Therefore, we must understand the evolution of this disorder. Normal gap acidosis can result either from losses of bicarbonate or inadequate buffering.

Reviewing bicarbonate losses, we find 2 causes:

1. Large-volume diarrhea. Since stool has a basic pH, it contains bicarbonate. With large-volume diarrhea (most common in infants or anyone who has cholera or cholera-like diarrhea), patients can develop a normal gap acidosis.

2. Proximal (type 2) renal tubular acidosis (RTA). In proximal RTA, the patient has a lowered bicarbonate level, above which bicarbonate will appear in the urine.

We also review inadequate buffering:

1. Ammonia creation and renal processing

A. The main variable renal buffer of acid is ammonium (NH4 +). The ammonium comes from the protonation of ammonia (NH3).

B. The ammonia comes from the metabolism of glutamine to alpha ketoglutarate. This reaction is controlled by the enzyme glutaminase. The reaction occurs in proximal tubular cells.

C. The ammonia passes into the proximal tubule, and is protonated to ammonium.

D. The ammonium is secreted into the medulla at the sodium potassium 2 chloride cotransporter site in the loop of Henle. There it reverts to ammonia and becomes part of the countercurrent mechanism. Thus, the concentrations of ammonia are greater in the medulla than in the cortex.

E. In the collecting duct, the ammonia returns and is once again protonated to ammonium.

2. There are 3 renal mechanisms for normal gap acidosis.

A. Inadequate buffering in the kidney can be caused by 3 potential problems. First, the patient can have decreased production of ammonium in the proximal tubule. Second, if the countercurrent mechanism has a decreased gradient (as in chronic kidney disease), the patient then has a low concentration of ammonia in the medulla, and there will be less buffering in the excreted urine. Finally, if the urine is not adequately acidified, the buffer will not work efficiently.

B. Patients with progressive chronic kidney disease have both a decrease in proximal tubular metabolic creation of ammonium and a decreased medullary gradient, which also decreases total buffering capacity. Patients who have hyperkalemia have decreased ammonia production because high potassium inhibits the action of the enzyme glutaminase. Finally, patients who cannot acidify their urine will have decreased buffering capacity. With incomplete distal acidification, the efficiency of buffering is greatly decreased; thus, the daily acid intake is incompletely buffered, eventually leading to a metabolic acidosis.

Third, we must distinguish between stool losses of bicarbonate and decreased buffering capacity. The classic way to do this is by calculating the urine anion gap. In our patient, we find that the urine anion gap = (25+45) - 38 = 32. This positive value is consistent with very low urine ammonium.

Fourth, the low urine ammonium tells us that we have a buffering problem. Calculating the urinary anion gap, as shown in the following equation, may be quite useful in providing an estimate of urinary ammonia secretion:

Urinary anion gap = (urinary [Na+] + urinary [K+]) - urinary [Cl-] -- omitted

Whenever secreted hydrogen ions are excreted as ammonium chloride (NH4 +Cl-), an increase in urinary chloride excretion results. The increase in urinary chloride excretion decreases the urinary anion gap, leading to a negative value in most patients with diarrhea. By comparison, in distal (type 1) RTA, the urinary anion gap is positive. As an example, a patient with a normal anion gap metabolic acidosis (eg, [HCO3 -] = 10 mEq/L), a low potassium level (hypokalemia), and an alkaline urine pH (6.0) could have diarrhea or type 1 RTA. If the following values were observed: urine [Na+] 50 mEq/L, urine [K+] 28 mEq/L, and urine [Cl-] 55 mEq/L, the urinary anion gap would be +23, supporting a diagnosis of RTA.

Another way to consider the urine anion gap is to remember that a positive value occurs when little NH4 + is present in the urine. These patients have a buffering problem. Patients with diarrhea have high NH4 +, so they have a negative urine anion gap. The relatively high urine pH in the face of a normal gap acidosis tells us that we have a defect in urine acidification -- or a distal RTA.

Finally, in reviewing the patient's history, we note that he is receiving amphotericin B, which is a known cause of distal RTA.

Thus, this patient has 2 problems: central diabetes insipidus secondary to cryptococcal meningitis, and distal RTA secondary to amphotericin B.

Read and participate in the discussion of this case here, and watch for another new case soon.

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