Detective Nephron: Hypernatremia

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Detective Nephron, world-renowned for his expert analytic skills, trains budding physician-detectives in the diagnosis and treatment of kidney diseases. L.O. Henle, a budding nephrologist, presents a new case to the master consultant.

NephronNephrology seems to be attracting fewer medical students and residents. I wonder why? It’s such a fascinating field. We need to do something as a community.
L.O. Henle enters the room.
NephronHenle, why did you choose nephrology as your career path?
HenleI enjoy the variety it has to offer. My mentors in the past left an impression on me, and you are cultivating it more. I love it. Now I have a case for us.
NephronGreat—what do you have for us?
HenleHypernatremia.
NephronOh, nice!
HenleA 45-year-old with a sodium level of 180 mmol/L, and he was completely asymptomatic. I shall stop there, as you usually suggest.
NephronIn hypernatremia, I think of osmostat/thirst, antidiuretic hormone (ADH) and/or the kidney as potential culprits. Of course, the problems with ADH can be in the production or responsiveness. But first, let me ask a simple question. Do you think the hypernatremia is due to a positive balance of sodium?
HenleNo, he was not given hypertonic saline, nor did he ingest excessive sodium bicarbonate.
NephronAh-ha! Now, has there been any nonrenal water loss?
HenleNot at all. He had no signs of gastrointestinal loss from vomiting or diarrhea, no sweating or hyperventilation. And no renal losses either. He is not taking any loop diuretic, nor is there any evidence of osmotic diuresis.
Nephron (chuckling)No, my dear apprentice. You might want to stop a bit and think back to the renal causes.
HenleDid you mean water shift into the intracellular fluid compartment, perhaps due to rhabdomyolysis and/or convulsions? If so, the creatine phosphokinase and lactate levels were normal, with no signs of that at all.
NephronWow, you really are taking the fun out of this. When you said renal losses, did you mean inappropriate renal water losses as in nephrogenic and central diabetes insipidus (DI)?
HenleOh, I see. So now you are done with ruling out primary sodium gain and nonrenal losses, and we are now thinking of possible renal losses via lack of ADH or inaction of ADH.
NephronI believe you!
HenleLet me start with the kidney first, as that’s easier. To my knowledge, he is not significantly polyuric; he makes only approximately 1 L of urine daily. His urine osmolarity is 1100 mOsm/kg.
NephronSo do you think the kidney is the culprit?
HenleJust to add, he doesn’t take lithium or a loop diuretic. He doesn’t have any hypercalcemia or hypokalemia and shows no signs of abnormal renal function. He is not taking any medications such as phenytoin that interfere with ADH production, and he’s had no recent brain trauma. Like I said—completely asymptomatic. Given his hypernatremia, a high urine osmolarity, and a relatively low urine flow, I think I can safely discard DI. If he indeed was polyuric, with a urine osmolarity lower than serum osmolarity, I would consider it an ADH problem. In that case, a desmopressin test would help differentiate a loss of ADH production or ineffective ADH response in the kidney. But the urine osmolarity is high in this case and close to maximum response. So, there is ADH on board, and it is effectively working on the kidneys. Hmmm.
NephronGood work, my friend. So you are telling me that he doesn’t have any signs of DI. You have shown that he has an intact ADH axis and that his tubules are responsive to ADH, and now you are going to test…? Well… what is his serum osmolarity?
Henle375 mOsm/kg.
NephronSo, you have someone here who walked into your office with a sodium level of >170 mmol/L and a significantly elevated serum osmolarity and normal ADH response. Is this person thirsty?
HenleNo; as I said before, he is completely asymptomatic. You are right. His thirst mechanism should have been activated with those numbers.
NephronTight regulation of water balance is accomplished via the thirst mechanism and ADH. Both are crucial to maintaining a remarkably narrow range of plasma osmolarity of 282–298 mOsm/kg. Osmoregulation of ADH is mediated by osmoreceptors located in the anteromedial hypothalamus near the neurohypophyseal cell bodies in the supraoptic nucleus. These osmoreceptors are extremely sensitive to changes in osmotic pressure. For example, an increase in osmolarity of 1 to 2 percent increases ADH secretion. However, ADH secretion alone is not adequate to prevent dehydration, and an intact thirst mechanism is vital for water homeostasis.
HenleThirst is a major player as well. Right?
NephronThirst is regulated by hypothalamic osmoreceptors that are sensitive to changes in effective osmotic pressure of body fluids. The osmotic threshold at which the thirst mechanism is activated begins approximately 5–10 mOsm higher than the threshold for ADH release. These two systems work together to maintain plasma osmolality. With both systems intact, hypernatremia is a rare development, but can occur in patients who have lost their ability to maintain or increase free water intake, for example hospitalized patients and particularly the geriatric population. Much rarer causes of hypernatremia from decreased intake are the adipsic disorders. These disorders result from alterations in the thirst mechanism that prevent patients from taking in adequate free water despite elevations in plasma osmolarity. Should I continue?
HenleHmm; so you are telling me that he has net primary water loss caused by a thirst disorder. Should I arrange for imaging of the brain? Could he have a lesion that is destroying the thirst center?
NephronDefects in ADH synthesis or secretion cause central DI (CDI) or in some instances partial CDI. These patients are polyuric and cannot concentrate their urine but maintain normal serum osmolarity by drinking large amounts of water. Their thirst mechanism is intact. These patients do relatively well until they physically cannot drink water or their access to free water is lost. Conversely, a lesion in the thirst center in the hypothalamus can lead to an abnormal or no thirst response to hyperosmolarity but a normal ADH response. A defect in osmoregulated thirst mechanism is termed hypodipsic or adipsic hypernatremia. It is frequently associated with defective ADH production as well, either CDI or partial DI. Because of their lack of thirst sense, patients with this condition may fail to drink spontaneously and are at risk of hypernatremia.
HenleSo, it is very likely this person has an adipsic hypernatremia.
NephronThere are four variants of adipsic hypernatremia. Type A adipsia is characterized by an upward setting of the osmotic threshold for both thirst and vasopressin release, sometimes called essential hypernatremia. Type B adipsia is characterized by subnormal thirst and vasopressin responses to osmotic stimuli. This is due to partial destruction of the osmoreceptors. Complete destruction of these receptors is classified as type C adipsia, and these patients have complete absence of ADH release and a lack of thirst mechanism. Type D is an extremely rare form that manifests as only a thirst mechanism failure with an intact ADH production. It seems that our friend here has a good intact ADH release—right?
HenleI agree. What lesions in the brain cause adipsia?
NephronClassically the ones reported are sarcoidosis, craniopharyngioma, anterior communicating artery aneurysm (ACOM), traumatic injury, and prolactinomas.
HenleGiven his age, the most likely cause is an ACOM.
NephronLet me know when you find out.
Henle exits without questioning.
Nephron (to himself)What a mix of endocrinology and nephrology! This is why renal medicine is fun.
A day later:
NephronYou’re back.
Henle (very excited)Magnetic resonance imaging of the brain confirmed ACOM.
NephronGood work!
HenleNow what?
NephronForced drinking to make him eunatremic—that is, scheduled water drinking because there is no thirst mechanism, with some desmopressin if need be—is usually what helps. But he might need some surgical intervention here.
HenleNothing is better than a cup of warm coffee. And a great case! And that’s usually your line.
NephronGreat work, Henle. Again, my dear apprentice, never underestimate the power of the nephrologist. Again, you made a marvelous discovery of a central nervous system finding from a single electrolyte disorder. The power of nephrology continues!
Detective Nephron was developed by Kenar Jhaveri, MD, assistant professor of medicine at Hofstra North Shore LIJ School of Medicine. Thanks to Dr. Michael Gitman, assistant professor of medicine at Hofstra North Shore LIJ School of Medicine, and Dr. Rimda Wanchoo, instructor of medicine at Weill Cornell Medical Center for their editorial assistance. Send correspondence regarding this section to kjhaveri@nshs.edu or kdj200@gmail.com.
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