Question:

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Nephrologists at a research hospital are investigating the physiologic changes that occur in diabetes insipidus. The group develops a technique that permits sampling of tubular urine in experimental animals with physiology similar to that of humans. The animals then undergo hypophysectomy, after which tubular fluid samples are obtained from multiple sites throughout the nephron. In the absence of antidiuretic hormone, fluid from which of the following sampling sites is most likely to have the highest osmolarity?

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Explanation:

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Tubular fluid osmolarity varies along the different segments of the nephron depending on each segment's permeability to water, the osmolarity of the renal interstitium, and the presence or absence of antidiuretic hormone (ADH):

In the proximal tubule, water is passively reabsorbed along with active transport of solutes into the interstitium. Fluid in the proximal tubule lumen is therefore isoosmotic with plasma (Choice A).

The descending limb of the loop of Henle is permeable to water, but not solutes. As this segment of the nephron descends into the medullary interstitium, water moves down its concentration gradient from the lumen into the highly osmotic medulla. No reabsorption of electrolytes occurs in this segment, so the fluid in the lumen becomes hypertonic (Choice B). However, tubular fluid will be the most concentrated at the bottom of the loop of Henle where interstitial osmolality is the greatest.

The thick ascending limb of the loop of Henle is impermeable to water. In this portion of the nephron, electrolytes are actively resorbed by the Na⁺/K⁺/2Cl^- cotransporter, causing the osmolarity of the tubular fluid to decrease and become hypotonic (Choice D).

Reabsorption of solutes continues to occur in the distal convoluted tubule through the action of the NaCl symporter. Because the early distal convoluted tubule is impermeable to water, tubular fluid increases in hypotonicity in this segment of the nephron (Choice E).

The water permeability of the collecting ducts depends on the presence of ADH. In the absence of antidiuretic hormone (ADH) (eg, overhydration, diabetes insipidus), the collecting ducts are impermeable to water, even when passing through high-osmolarity regions within the medullary concentration gradient. As solutes continue to be removed, tubular fluid in this segment can become as hypotonic as 50 mOsm/L, producing a very dilute urine.

(Choice F) When ADH levels are high (eg, dehydration), the collecting duct is highly permeable to water. Water leaves the tubular fluid driven by the high osmolarity of the medullary interstitium, and hypertonic urine is formed (up to 1200 mOsm/L). However, in this experiment the hypophysectomized animals are unable to produce ADH and will have dilute urine.

Educational objective:
Antidiuretic hormone (ADH) acts primarily on the collecting ducts, increasing their permeability to water. In the absence of ADH, the tubular fluid is most concentrated at the junction between the descending and ascending limbs of the loop of Henle and most dilute in the collecting ducts.