How does hypercalemia cause nephrogenic diabetes?

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The explanation states that Ca+2 accumulates in the inner medulla and paipilla of the kidney to inhibit adenyl cyclase. Can someone explain to me how this inhibition occurs?

Originally Posted by HelpPleaseMD

The explanation states that Ca+2 accumulates in the inner medulla and paipilla of the kidney to inhibit adenyl cyclase. Can someone explain to me how this inhibition occurs?

I've actually never heard of that before. Which resource (and where) says that?

I could imagine that increased intracellular charge would shift the equilibrium to the left to disfavor G-alpha-s activation.

However, yet again, with respect to nephrogenic DI, I've still never heard of that.

BRS physio question 12 of the comprehensive exam on the back. Its implied when she explains the question

This was in one of the UWSAs as well. No idea. Even uworld didn't explain it.

Originally Posted by HelpPleaseMD

The explanation states that Ca+2 accumulates in the inner medulla and paipilla of the kidney to inhibit adenyl cyclase. Can someone explain to me how this inhibition occurs?

Lithium causes NDI by the same mechanism.

Originally Posted by thinkenergy

Lithium causes NDI by the same mechanism.

Inhibition of the phosphatidyl inositol cascade?

That just can't be right...

Where did you read that?

I would think that since lithium is a group ONE metal, if anything, sodium would demonstrate a greater propensity to act via that same pathway, versus calcium or magnesium, which are both group two alkalis.

Also, if hypercalcemia causes nephrogenic DI, why are thiazides (ie. calcium-retaining diuretics) the first line treatment (FA 328)? I understand that they increase NaCl reabsorption in the distal tubule to decrease diluting capacity, which is helpful since the problem stems from being unreceptive to ADH and unable to concentrate the urine.

Maybe these work if the nephrogenic DI is caused by anything besides hypercalcemia, and indomethacin/amiloride are used if hypercalcemia is the primary problem?

Sorry if that was confusing. I'm obviously confused about this whole mechanism

Originally Posted by Phloston

I've actually never heard of that before. Which resource (and where) says that?

I could imagine that increased intracellular charge would shift the equilibrium to the left to disfavor G-alpha-s activation.

However, yet again, with respect to nephrogenic DI, I've still never heard of that.

Does this mean it isn't possible?

Hypercalcemia causes nephrogenic DI through the downregulation of aquaporin-2 channels as well as tubulointerstitial injury caused by calcium deposition.

Originally Posted by Phloston

Inhibition of the phosphatidyl inositol cascade?

That just can't be right...

Where did you read that?

I would think that since lithium is a group ONE metal, if anything, sodium would demonstrate a greater propensity to act via that same pathway, versus calcium or magnesium, which are both group two alkalis.

Both Li and Ca inhibits adenylate cyclase, leading to decreased cAMP, w/o cAMP as 2nd messenger, V2 receptor (Gs) downstream signaling is blocked. This is why. It has nothing to do w/ IP3 mechanism.

Also HCTZ is used for non-Li-induced NDI, amiloride is used for Li-induced NDI, the rationale is that since amiloride blocks ENaC in DT & CD, there is higher Na+ in ductal lumen, and b/c Na & Li compete for reaborption, high Na+ competitive inhibits Li reaborption. HCTZ is not used b/c it increase distal Na delivery resulting in higher than normal Na reabsorption in DT & CD, this facilitates Li reaborption.

To answer the paradoxical question why HCTZ is used for NDI even though it causes hypercalcemia, it is really simple. HCTZ induces production of hyperosmotic urine, remember it acts on the diluting segment, so by preventing polyuira, HCTZ is acting in a way to conserve free water though not directly on the CD.

Originally Posted by thinkenergy

Both Li and Ca inhibits adenylate cyclase, leading to decreased cAMP, w/o cAMP as 2nd messenger, V2 receptor (Gs) downstream signaling is blocked. This is why. It has nothing to do w/ IP3 mechanism.

Also HCTZ is used for non-Li-induced NDI, amiloride is used for Li-induced NDI, the rationale is that since amiloride blocks ENaC in DT & CD, there is higher Na+ in ductal lumen, and b/c Na & Li compete for reaborption, high Na+ competitive inhibits Li reaborption. HCTZ is not used b/c it increase distal Na delivery resulting in higher than normal Na reabsorption in DT & CD, this facilitates Li reaborption.

To answer the paradoxical question why HCTZ is used for NDI even though it causes hypercalcemia, it is really simple. HCTZ induces production of hyperosmotic urine, remember it acts on the diluting segment, so by preventing polyuira, HCTZ is acting in a way to conserve free water though not directly on the CD.

Thanks. Great explanation!

This seems like it's beyond Step 1 but I looked into it a bit out of curiosity:

Goldman: Goldman's Cecil Medicine, 24th ed.

Nephrogenic diabetes insipidus can also be acquired during treatment with certain drugs, such as demeclocycline... and from electrolyte abnormalities such as hypokalemia and hypercalcemia. All causes of acquired nephrogenic diabetes insipidus have in common the decreased synthesis and function of aquaporin-2 due to impaired vasopressin signaling from V2 receptor binding and activation

Acquired nephrogenic diabetes insipidus. -Khanna A.

Similar to hypokalemia another electrolyte disorder, hypercalcemia, also is associated with the development of NDI. An experimental model of vitamin D–induced hypercalcemia has been used to study the molecular defects underlying the NDI seen in this disorder.27 Rats treated orally for 7 days with dihydrotachysterol showed a 3-fold increase in urine production, along with a 50% reduction in urine osmolality. Consistent with this, immunoblotting of membrane fractions showed a 50% reduction in AQP2 expression in kidney inner medulla from hypercalcemic rats. Wang et al28 have elucidated the molecular mechanism of this disorder further. They showed that in addition to downregulation of collecting duct AQP2 expression, there was also a significant downregulation of the bumetanide-sensitive Na-K-2Cl cotransporter BSC-1 in membranes from inner the stripe of the outer medulla. This defect in the thick ascending limb may participate in the development of the urinary concentrating defect.

Extracellular calcium antagonizes forskolin-induced aquaporin 2 trafficking in collecting duct cells --Giuseppe Procino

Results We demonstrated that extracellular calcium (Ca2+o) (5 mmol/L) strongly inhibited forskolin-stimulated increase in AQP2 expression in the apical plasma membrane. At least three intracellular pathways activated by extracellular calcium were found to contribute to this effect. Firstly, the increase in cAMP levels in response to forskolin stimulation was drastically reduced in cells pretreated with Ca2+o compared to untreated cells. Second, Ca2+o activated PKC, known to counteract vasopressin response. Third, quantification of F-actin demonstrated that Ca2+o caused a nearly twofold increase in F-actin content compared with basal conditions. All these effects were mimicked by a nonmembrane permeable agonist of the extracellular CaR, Gd3+.

Originally Posted by thinkenergy

Both Li and Ca inhibits adenylate cyclase, leading to decreased cAMP, w/o cAMP as 2nd messenger, V2 receptor (Gs) downstream signaling is blocked. This is why. It has nothing to do w/ IP3 mechanism.

Also HCTZ is used for non-Li-induced NDI, amiloride is used for Li-induced NDI, the rationale is that since amiloride blocks ENaC in DT & CD, there is higher Na+ in ductal lumen, and b/c Na & Li compete for reaborption, high Na+ competitive inhibits Li reaborption. HCTZ is not used b/c it increase distal Na delivery resulting in higher than normal Na reabsorption in DT & CD, this facilitates Li reaborption.

To answer the paradoxical question why HCTZ is used for NDI even though it causes hypercalcemia, it is really simple. HCTZ induces production of hyperosmotic urine, remember it acts on the diluting segment, so by preventing polyuira, HCTZ is acting in a way to conserve free water though not directly on the CD.

To the bold, GunnerTraining, a source I used has a clear explanation:

Paradoxical Antidiuretic Effect of Thiazides in Diabetes Insipidus: Another Piece in the Puzzle
http://jasn.asnjournals.org/content/15/11/2948.full

Nephrogenic DI (diabetes insipidus)—Why treat a water-wasting disease with a diuretic? Thiazides increase renal Na excretion → ECF volume contraction → ↓ GFR → ↑ proximal tubular reabsorption of water and Na ∴ less water and Na are lost as urine

To your quote:

Originally Posted by thinkenergy

Both Li and Ca inhibits adenylate cyclase, leading to decreased cAMP, w/o cAMP as 2nd messenger, V2 receptor (Gs) downstream signaling is blocked. This is why. It has nothing to do w/ IP3 mechanism.

I think this is incorrect, the IP3 mechanism is involved if you look at the research above.

Second, Ca2+o activated PKC, known to counteract vasopressin response.

Originally Posted by HelpPleaseMD

The explanation states that Ca+2 accumulates in the inner medulla and paipilla of the kidney to inhibit adenyl cyclase. Can someone explain to me how this inhibition occurs?

I think you simply need to know the high yield facts to answer this question. Li,Ca & Na are, for our purposes, cause similar pathology in kidneys when in excessive amounts due to their relationship on the periodic table.

Originally Posted by Azipropofol

I think you simply need to know the high yield facts to answer this question. Li,Ca & Na are, for our purposes, cause similar pathology in kidneys when in excessive amounts due to their relationship on the periodic table.

Exactly, the exact mechanisms are very difficult to find other than knowing the buildup leads to inhibition of certain 2nd messenger pathways that upregulate that aquaporin.

Thanks

I like how I'm seeing my reply from May 2012 in this thread and didn't know, but I've actually encountered this before. It was UWorld I believe (as VisionaryTics has mentioned, he may have seen it in one of the UWSAs), and it was a question that 16-20% got right - something ridiculously low.

As far as I'm aware, there's direct tubular damage secondary to the hypercalcaemia. That's the extent to which I remember it.

Maybe someone will take the plunge/time and PubMed it....

so is this different from the hypercalcemia-->nephrocalcinosis-->nephrogenic diabetes insipidus mechanism taught in pathoma?

Edit: just saw phloston's post #16 above. That's what I was taught, too.

Calcium decreases the renal concentrating ability by inhibiting the response to ADH
2) By reducing medullary tonicity (via decreasing NaCl absorption in the loop of Henle).