BRCU 2026: Test Your Knowledge
A 35-year-old man with human immunodeficiency virus infection (HIV) was recently started on a tenofovir-based HIV treatment regimen and posaconazole for oropharyngeal candidiasis. After 3 weeks of therapy, he developed nausea and vomiting. His laboratory values were as follows: Na, 138 mmol/L; K, 2.4 mmol/L; Cl, 96 mmol/L; HCO3, 32 mmol/L. An arterial blood gas showed a pH of 7.47, PCO2 of 45 mm Hg, and an HCO3 of 32 mmol/L. The urine Cl was 46 mmol/L. Renin and aldosterone levels were both depressed. On examination he did not appear ill but had a BP of 150/100 mm Hg, which was previously normal.
What is the likely cause of these electrolyte and acid base abnormalities?
- Vomiting
- Tenofovir-induced proximal tubulopathy
- Gitelman syndrome
- Licorice-induced hyperaldosteronism
- Posaconazole-induced hypercortisolism
Show Answer
Reference:
-
1) Young WF. Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion). Post TW, ed. UpToDate. Waltham, MA: UpToDate
-
2) Cely CM, Contreras G. Approach to the patient with hypertension, unexplained hypokalemia, and metabolic alkalosis. Am J Kidney Dis.2001;37(3):E24
Ready to Learn More?
Board Review Course & Update (BRCU) is a comprehensive, three-day, in-person course focused on key nephrology concepts that prepare you for the ABIM nephrology certification and recertification exams, as well as the Longitudinal Knowledge Assessment (LKA). Join colleagues in Chicago, IL, to face your boards with confidence.
Learn More
Register
Explanation
There are many important teaching points to this case. This patient has a metabolic alkalosis with respiratory compensation, also with hypertension (HTN) and a high urine Cl, indicating a chloride unresponsive metabolic alkalosis. The anion gap is normal so there is not a simultaneous hidden anion gap metabolic acidosis. The high urine Cl makes vomiting (option 1) an incorrect choice, as vomiting is a chloride responsive alkalosis. Additionally, the renin and aldosterone would be elevated from volume depletion, which was not the case. Tenofovir (option 2) has many tubular toxic effects, but these are predominantly on the proximal tubule and would cause a metabolic acidosis (or a full Fanconi syndrome) not an alkalosis. Gitelman syndrome (option 3) can present at any time in adulthood with hypokalemic metabolic alkalosis and would have a high urine Cl, but the renin and aldosterone would be high and BP would be low/normal from tubular sodium loss.
The combination of high renin and high aldosterone is seen in malignant HTN, renal artery stenosis, and the very rare condition of a renin-producing tumor (reninoma). This patient had both low renin and aldosterone, which takes the answer to this case out of this differential. Hypokalemic metabolic alkalosis associated with HTN indicates excessive mineralocorticoid activity. The most common cause of this would be from primary hyperaldosteronism, but the aldosterone would be high and the renin would be low in this condition. This pattern of high aldosterone and low renin is seen in glucocorticoid-suppressible hyperaldosteronism. These are ruled out by both renin and aldosterone being suppressed. When you see the clinical effects of excessive mineralocorticoid (hypokalemia, metabolic alkalosis, and HTN) yet aldosterone is suppressed, you should be considering the "syndrome of apparent mineralocorticoid excess" (AME). In AME, something other than aldosterone is acting as aldosterone and thus suppressing its production along with renin. These represent an uncommon group of conditions that include genetic, ingestions, and malignant etiologies. Liddle syndrome is a rare autosomal dominant disease involving an overactive epithelial sodium channel (ENaC) in the collecting duct. Geller syndrome is an even rarer autosomal dominant disease related to a gain of function mutation of the aldosterone receptor. These two congenital conditions would present with HTN in childhood and will have a strong family history of HTN. Rare malignant adrenal tumors that produce large deoxycorticosterone that has mineralocorticoid activity will have a similar effect as will the administration of high doses of a nonaldosterone mineralocorticoid agonist (e.g., fludrocortisone).
The final group conditions that fit into this low renin, low aldosterone hypokalemic metabolic alkalosis with HTN syndrome are related to the interruption of a very interesting and important physiologic process. Cortisone is the main glucocorticoid released by the adrenal gland, but it has strong mineralocorticoid effects in the kidney. To prevent this untoward effect, the kidney possesses the enzyme 11-β-hydroxysteroid dehydrogenase 2 that converts cortisol to cortisone, which has no mineralocorticoid activity. If you have an adrenocorticotrophic hormone (ACTH)-producing tumor, the adrenal gland may make so much cortisol that 11-β-hydroxysteroid dehydrogenase 2 is overwhelmed and cannot adequately convert all the excessive cortisol to cortisone. The final way is to increase cortisol's effect in the kidney is to decrease the effectiveness of the normal enzyme. A rare autosomal recessive condition is a congenital mutation in this enzyme in which it cannot adequately convert normally produced cortisol to cortisone. This should present as HTN in childhood, although because it is autosomal recessive, a family history of HTN may not be present. The enzyme can also be affected by glycyrrhizic acid, a potent inhibitor of 11-β-hydroxysteroid dehydrogenase 2, which is found in licorice or licorice-flavored products (e.g., some liquors and chewing tobacco). Option 4 is wrong because the mineralocorticoid effects of the increased intrarenal cortisol would suppress aldosterone and not increase it. More recently, the antifungal drugs posaconazole (correct option 5) and itraconazole have shown to similarly inhibit 11-β-hydroxysteroid dehydrogenase 2 and produce this syndrome.
There is a differential diagnosis of HTN with hypokalemia and chloride-unresponsive metabolic alkalosis based on renin and aldosterone profiles (from reference 2).
