Why Do Thiazides Decrease Polyuria in Diabetes Insipidus?

I was reviewing the treatment of diabetes insipidus the other day, and was reminded of the paradoxical effect of thiazide diuretics on urine output in diabetes insipidus. How does this work? The traditional thinking is that thiazide-induced blockade of the Na-Cl cotransporter in the distal tubule leads to a decrease in GFR. This decrease is compensated by an increase in proximal tubule sodium and water uptake. Because less water and solute are then delivered to the collecting duct, less water is lost as urine. However, some studies suggest that chronic use of thiazides does not result in a decrease in extracellular fluid volume: cardiac output returns to normal several weeks after initiating therapy, and infusion of salt-free dextran does not increase blood pressure. Studies in rats with central DI have also shown that replacement of renal sodium losses does not prevent the antidiuretic effect of thiazides.

Experiments by Kim et al. suggest that thiazides may serve to upregulate aquaporin channels and ENaC subunits. In rates with lithium-induced nephrogenic DI, HCTZ reversed lithium-induced downregulation of AQP2. It also caused an increase in the abundance of ENaC channels. While these results are specific to Li-induced renal effects, they may at least partially explain how a thiazide can serve to decrease polyuria in patients with diabetes insipidus.

7 comments

  1. Diazides at usual dosage (25 – 100 mg per day) decrease both the concentrating and diluting capabilities of the kidneys (make the urine isosthenuric or tonicity of 300 mOsm per liter.) Diabetes insipidus, be it central of nephrogenic results in a DILUTE urine (urine osmolality well below the isosthenuric 300 mOsm per liter.) This therapeutic effect is done by literally overwhelming the Na+ and H2O resorptive nephron sites through the diuretic effect. By doing this the hypertonicity of the blood, ECF and ICF is “ironed out” to normal levels by mass action. Of course, the patient must maintain good liquid intake. The use of NSAIDs may help by reducing reducing the diuretic effect of renal prostaglandins, but chronic use of NSAIDs can result in permanent renal damage (NSAID nephropathy), something we would not want to add onto a person who has this DI problem. DI can transiently follow strokes or chronic flouroquinolones which sre no longer recommended except in rare circumstances (treatment/prevention of Anthrax).

  2. Thiazides are usually prescribed as Diuretics because they inhibit the Na-Cl Cotransporter in the DCT which prevents their reabsorption and increases Osmolarity of Tubular fluid that decreases Water reabsorption and consequently the GFR.

    In case of NDI, our kidneys don’t respond to the ADH/Vasopressin hormone. This leads to polyuria as the concentrating ability of kidney is lost.

    We paradoxically give diuretic (Thiazide) to help prevent Polyuria. Here is how it works:
    1) Thiazides will increase the conc. of Na and Cl in the Tubular fluid at DCT
    2) Macula Densa cells of the Juxta medullary apparatus notice this increase in Na and Cl
    3) They release Adenosine
    4) Adenosine causes vasoconstriction of afferent arterioles
    5) GFR decreases

    The decrease in GFR leads to less availability of water for excretion that prevents Polyuria

  3. In Diabetes insipidus which leads to dilute urine( more water loss than salt). Less water has been reabsorbed through the distal renal tubules and collecting ducts ( water permeability decreased…) while Na reabsorption (through the Distal Renal tubules and Collecting ducts) is normal so it gets back easily to the bloodstream.Therefore, the blood is going to be hyperconcentrated ( as water always follows sodium, lol, High Sodium concentration is going to pull water inside of the blood vessels(causing high blood pressure due to the increase of blood volume) and that situation would lead normally to dehydration so the role of the Thiazides is to regulate the electrolyte and fluid balance disorder. Thiazides gonna help the patient to put out all the excess of Na from the blood through urine.

    According to my personal opinion, since Water is linked with Sodium, to eliminate one involves the elimination of both of them, the more you have Sodium in your blood, the more your urine gonna be.
    Diuretic effect of Thiazides depend on high blood salt concentration, down to some level of salt concentration, diuretic effect may become less even the drug effect maybe reversed. Studies result might be controversial at this point because of cofounding bias, further studies must be done in this area.

  4. ?

  5. Thank you.

  6. I think, that the problem with Thiazides use in treating Diabetes Indipidus(DI or NDI) is that you loose more H2O(water) than Na+(sodium) when you have NDI and the serum Osmolarity goes high and this Osmolarity process stimulates you to drink more H2O(water) (Polydipsia)thru indusing thirst, which of course causes Polyuria. Thiazides release Na+ binded with H2O, so to bring the Osmolarity down, which reduces your urge to drink and therefore you pee less. In short, the Thiazides breaks the Polydipsia-Polyuria cycle.Also other good medicine for this to use is Desmopressin.

    Some more information about NDI ca be found here: Nephrogenic Diabetes Insipidus (NDI) – What Is It, Causes, Symptoms, Diagnosis and Treatment.

  7. There are also studies that show thiazides DO decrease plasma volume on the long-run. So this is still controversial. Actually, research in mice shows that this is the mechanism for thiazide-induced hypocalciuria.

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