Welcome to USMLE practice question #140! Today’s topic is nephrology.
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A 50-year-old man presents with a 2-month history of excessive thirst and increased urination. He drinks more than 4 liters of water per day and frequently wakes up at night to urinate. Physical examination reveals dry mucous membranes, but no peripheral edema or orthostatic hypotension. Laboratory studies show the following:
• Serum sodium: 149 mEq/L (normal: 135–145 mEq/L)
• Serum osmolality: 310 mOsm/kg (normal: 275–295 mOsm/kg)
• Urine osmolality: 150 mOsm/kg (normal: 500–800 mOsm/kg)
• Serum glucose: 90 mg/dL (normal: 70–110 mg/dL)
After administering desmopressin, his urine osmolality remains unchanged. Which of the following best explains the underlying mechanism of his condition?
A) Reduced aquaporin-2 expression in the collecting ducts
B) Failure of proximal tubule sodium reabsorption
C) Autoimmune destruction of juxtaglomerular cells
D) Overactivation of ENaC in the collecting ducts
E) Excessive vasopressin degradation by renal enzymes
Detailed Breakdown of Answers + Correct Answer Below ⏬
ANSWER + QUESTION BREAKDOWN
It’s important to adopt the correct MENTAL MODEL when answering USMLE questions; it saves time and increases accuracy. The mental model outlined below is a foundational component of our test-taking skills masterclass (check it out if you want to elevate your skills). Here’s how to think through this question:
Step 1. Read the last line to get to the heart of the question: “Which of the following best explains the underlying mechanism of his condition?”
Step 2: Is this a first-, second-, or third-order question?
Answer: 2nd order. 1st: Make a diagnosis, 2nd: Identify the underlying cause
Step 3: Read the vignette carefully and ask yourself: “Based on the given information, the underlying mechanism of his condition is ______________.”
Step 4. Look at the answer choices and select the option most closely resembling your final thought from “Step 3” above.
GENERAL ANALYSIS
This 50-year-old man presents with excessive thirst and increased urination, with laboratory findings showing hypernatremia, elevated serum osmolality, and low urine osmolality. The inability to concentrate urine despite desmopressin administration indicates nephrogenic diabetes insipidus.
ANSWER CHOICES:
CHOICE A: Reduced aquaporin-2 expression in the collecting ducts
Explanation: In nephrogenic diabetes insipidus, mutations or dysfunction in the V2 receptor or downstream signaling pathways impair aquaporin-2 channel insertion into the apical membrane of collecting duct cells. This prevents water reabsorption, leading to polyuria and dilute urine despite normal or elevated ADH levels.
CHOICE B: Failure of proximal tubule sodium reabsorption
Explanation: Osmotic diuresis occurs when excess solutes (e.g., glucose in diabetes mellitus) are filtered into the urine and pull water with them due to osmotic effects. This patient has normal serum glucose levels, ruling out osmotic diuresis. Additionally, nephrogenic diabetes insipidus is caused by impaired water reabsorption in the collecting ducts, not by proximal tubule dysfunction.
CHOICE C: Autoimmune destruction of juxtaglomerular cells
Explanation: Autoimmune destruction of juxtaglomerular cells leads to reduced renin secretion and secondary hypoaldosteronism, causing hyperkalemia and hyponatremia. This patient has hypernatremia and dilute urine—findings inconsistent with hypoaldosteronism.
CHOICE D: Overactivation of ENaC in the collecting ducts
Explanation: Overactivation of epithelial sodium channels (ENaC) occurs in conditions like Liddle syndrome, leading to sodium retention, hypertension, and hypokalemia—this patient does not have hypertension or hypokalemia.
CHOICE E: Excessive vasopressin degradation by renal enzymes
Explanation: Excessive degradation of vasopressin could theoretically reduce its effect on the kidneys. However, this is not a recognized mechanism for nephrogenic diabetes insipidus.
FINAL VERDICT…
CORRECT ANSWER: A) Reduced aquaporin-2 expression in the collecting ducts
Nephrogenic diabetes insipidus results from defective V2 receptor signaling or downstream pathways that impair aquaporin-2 channel insertion into the apical membrane of collecting duct cells. This prevents water reabsorption and leads to polyuria and dilute urine despite normal or elevated ADH levels.
KEY CONCEPTS:
Pathophysiology of Nephrogenic Diabetes Insipidus (NDI):
Caused by mutations or dysfunction in:
Vasopressin type 2 receptor (V2 receptor).
Aquaporin-2 (AQP2) water channels.
Impairs water reabsorption in the collecting ducts.
Leads to excretion of large volumes of dilute urine despite normal ADH levels.
Clinical Features of NDI:
Polydipsia and polyuria.
Hypernatremia with elevated serum osmolality.
Low urine osmolality (<300 mOsm/kg).
Diagnostic Findings:
Water deprivation test: Inability to concentrate urine.
Desmopressin test:
Central DI: Urine osmolality increases.
Nephrogenic DI: Urine osmolality remains low.
Causes of NDI:
Congenital: Mutations in V2 receptor or AQP2 gene.
Acquired: Lithium toxicity, hypercalcemia, hypokalemia.
Management of NDI:
Address underlying cause (e.g., discontinue lithium).
Thiazide diuretics and low-sodium diet to reduce polyuria.
Amiloride for lithium-induced NDI.