Internal Medicine Correlations and Clinical Scenarios (CCS) USMLE Step 3

CASE 9: Renal Tubular Acidosis

Setting: hospital ward

CC: “My head hurts and the light hurts my eyes.”

VS: BP:152/92 mm Hg; P: 98 beats/minute; T: 102°F; R:18 breaths/minute

HPI: A 45-year-old man with acquired immunodeficiency syndrome (AIDS) is admitted to the hospital for fever, headache, and stiff neck. The head CT was done by the ED physician and was negative. Symptoms have been going on for 5 to 10 days. He is not adherent to his antiretroviral therapy. His CD4 count is “around 50 [cells/mm³],” but he has not seen a doctor for months.

CT before lumbar puncture (LP):

• Focal findings

• Papilledema

• Severe confusion

• Possibly in immunocompromised persons

PMHX:

AIDS

Oral thrush

Herpes simplex

Medications: nonadherent

PE:

General: uncomfortable, lying face down on stretcher

HEENT: photophobia and nuchal rigidity are present; fully alert; no focal findings detected

Initial Orders:

LP

Serum cryptococcal antigen

CD4 level

Genotyping

Genotype = HIV viral sensitivity testing

Advance the clock just enough to get the results of the LP. Although the most common cause of meningitis is Cryptococcus, you want to get the LP to quickly exclude bacterial meningitis.

What is the fastest way to tell the difference between bacterial and fungal meningitis?

• Cell count

• Thousands of Polymorphonuclear Leukocytes (PMNLs) = Bacterial Meningitis

• Ten to Hundreds of Lymphocytes = Fungal, Viral, Rickettsia

Report:

Cerebrospinal fluid (CSF): 117 × 10⁹/L WBCs, 94% lymphocytes

Opening pressure elevated

Gram stain negative

Protein elevated

Although this elevation of lymphocytes does not prove a patient has Cryptococcus, in the context of HIV, treatment for Cryptococcus is best. Do not wait for the results of cryptococcal antigen level.

The India ink capsule stain is 60% sensitive and an antiquated test.

Use the cryptococcal antigen test.

The India ink capsule stain uses the large, sugary glycocalyx around Cryptococcus to repel the ink.

What is the best initial therapy for Cryptococcus?

a. Caspofungin

b. Fluconazole

c. Amphotericin

d. Itraconazole

Answer c. Amphotericin

Amphotericin, often combined with 5-flucytosine (5-FC) is the best therapy for Cryptococcus. Caspofungin does not cover Cryptococcus. Fluconazole does not have as much efficacy and benefit in mortality as amphotericin.

Caspofungin inhibits 1,3-glucan linkage in the fungal cell wall.

Cryptococcus does not have this bond.

Amphotericin inhibits ergosterol in the fungal cell wall.

Amphotericin is started. The cryptococcal antigen comes back the next day markedly elevated. CD4 is 18 cells/mm³ and the genotype shows a fully sensitive virus. Antiretroviral drugs are started. After 5 days on amphotericin, the chemistry test results are:

Potassium 3.0 mEq/L (low)

Creatinine 2.1 mg/dL

Serum bicarbonate 18 mEq/L (normal 22−26 mEq/L)

Sodium 140 mEq/L

Chloride 112 mEq/L (elevated)

What causes this change in laboratory results?

a. Sepsis

b. Lactic acidosis

c. Amphotericin effect on the distal tubule

d. 5-Flucytosine toxicity

Answer c. Amphotericin effect on the distal tubule

Amphotericin use has a clear association with distal renal tubular acidosis (RTA). The anion gap is normal (Na⁺ 140 mEq/L) - (Cl^– 112 mEq/L + HCO^3– 18 mEq/L) = 10 mEq/L.

Sepsis and lactic acid give an elevated anion gap metabolic acidosis. The two most common causes of normal anion gap metabolic acidosis are diarrhea and RTA.

RTA and Diarrhea

• High chloride level

• Normal anion gap

Which test can be used to distinguish diarrhea and RTA as the cause of normal anion gap metabolic acidosis?

a. Serum bicarbonate level

b. Sodium level

c. Urine anion gap (UAG)

d. Response to antibiotics

Answer c. Urine anion gap (UAG)

UAG = Na⁺ – Cl^–

Na⁺ > Cl^– = Positive UAG = RTA

Na⁺ < Cl^– = Negative UAG = Diarrhea

UAG is based on the kidney excreting acid or hydrogen ion (H⁺) bound to ammonium chloride or NH₄Cl^–. In diarrhea, this mechanism works, because the kidney works. In RTA, the kidney does not work, so it cannot excrete acid.

The urine anion gap is the hardest thing to understand in nephrology.

Report:

Urine sodium level is greater than urine chloride level

Repeat potassium: 3.0 mEq/L

Distal RTA on amphotericin is an expected event.

Everyone gets it after a few days.

Amphotericin inhibits the ability of the distal tubule to excrete acid.

Which of the following should be found with amphotericin?

Answer b. Urine pH is high (>5.5), serum K is low, and stones can form.

Distal RTA is a defect in the ability of the kidney to excrete acid. This makes the urine pH alkalotic (Figure 6-4). In an alkalotic (pH > 5.5) urine, stones are more likely to form. In most types of distal RTA, you can treat with bicarbonate because the proximal tubule is where the bicarbonate is absorbed and it still works. This is why distal RTA can be treated with bicarbonate if you cannot reverse the cause.

Figure 6-4. Schematic representation of channels, transporters, and enzymes associated with hereditary renal tubular disorders. AA, amino acids; AE1, anion exchanger 1; AT1, amino acid transporter; CA (II), carbonic anhydrase II; CLC-5, chloride channel 5; CLC-Kb, chloride channel Kb; NCCT, thiazide-sensitive Na-Cl co-transporter; rBAT, renal basic amino acid transport glycoprotein; RTA, renal tubular acidosis; TRPM6, transient receptor potential cation channel, subfamily M, member 6. (Reproduced with permission from Longo DL, et al. Harrison’s Principles of Internal Medicine, 18th ed., Vol. 2. New York: McGraw-Hill; 2012.)

In proximal RTA (choice a) the urine pH rises when bicarbonate is administered because the kidney is not able to absorb it. This is why proximal RTA cannot be fully treated with just giving bicarbonate. The patient will not be able to absorb it. Because the urine ends up being acidotic (pH < 5.5) after all the bicarbonate runs out of the body, stones are not formed. Stones more often form in a higher urine pH.

Replace potassium. Everyone on amphotericin for more than a few days develops a reversible distal RTA and will need potassium replacement. After 7 to 10 days, you can safely switch the amphotericin to oral fluconazole, and the RTA and increased creatinine should all spontaneously resolve.

Distal RTA of amphotericin is self-limited after stopping it.

• Proximal RTA is treated with diuretics.

• Diuretics induce volume contraction and increase aldosterone.

• Increased aldosterone excretes acid at the distal tubule.