Polyuria is considered a classic symptom of hypercalcemia and was one of the symptoms described in the first published case of hyperparathyroidism (1). Several potential mechanisms may explain this phenomenon.

The calcium sensing receptors (CaSRs) found in the kidney play a major role in volume status due to their expression in the thick ascending loop (TAL) of Henle and the collecting duct. Interestingly, hypercalcemia activates the CaSR in the medullary portion of TAL, causing inhibition of the same cotransporter (Na-K-2Cl) inhibited by furosemide and other loop diuretics (2-4)! Hypercalcemia also inhibits vasopressin action ( therefore urine concentration) by activating CaSR in the collecting duct (5).  Lastly, inhibition of Na⁺-K⁺ ATPase in the proximal convoluted tubule may further contribute to natriuresis and subsequent polyuria.

Thus, hypercalcemia may lead to polyuria by interfering with the absorption of sodium as well as inhibiting the action of vasopressin.  One can’t help but compare its effect to that of a patient with diabetes insipidus taking a loop diuretic!  No wonder these patient may suffer from polyuria!

Contributed by Michael Hughes, Medical Student, Harvard Medical School

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REFERENCES

1. Goldfarb S, Agus ZS. Mechanism of the polyuria of hypercalcemia. Am J Nephrol. 1984;4:69-76. https://www.karger.com/Article/Abstract/166780 
2. Quamme GA. Effect of hypercalcemia on renal tubular handling of calcium and magnesium. Can J Physiol Pharmacol. 1982;60:1275-80. https://pubmed.ncbi.nlm.nih.gov/7172116/ 
3. Peterson LN. Vitamin D-induced chronic hypercalcemia inhibits thick ascending limb NaCl reabsorption in vivo. Am J Physiol. 1990;259:122-9. https://ur.booksc.eu/book/74535613/d202af 
4. Riccardi D, Brown EM. Physiology and pathophysiology of the calcium-sensing receptor in the kidney. Am J Physiol Renal Physiol. 2010;298:485-99. https://pubmed.ncbi.nlm.nih.gov/19923405/ 
5. Toka HR, Pollak MR, Houillier P. Calcium sensing in the renal tubule. Physiology (Bethesda). 2015;30:317-26. https://pubmed.ncbi.nlm.nih.gov/26136545/ 

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