Oh Mg (part 1)

By RWH

January 12, 2020 - 3 minutes read - 516 words

In this post…

PPIs are associated with hypomagnesaemia
PPIs reduce intestinal Mg²⁺ absorption
diuretics, CNIs and anti-cancer agents promote renal Mg²⁺ loss

PPIs and Mg

We had a referral recently for a case of persistent hypomagnesaemia “? cause”. As is often the case, the patient had been taking a PPI for some years. There was no obvious alternative explanation and FE_Mg was low - so we blamed this as the likely culprit. But was this just lazy? It was a prompt to review the literature regarding the strength of the association between PPI use and hypomagnesaemia and the underlying molecular mechanism.

Do PPIs cause hypomagnesaemia?

PPIs are taken by millions world-wide are generally pretty safe. We know from RCTs such as the COMPASS trial that adverse effects are relatively rare, but that PPIs do cause a small increase in the risk of enteric infections.

There is an association between PPI use and hypomagnesaemia: an association that is potentiated by concomitant use of diuretics. Although rooted in observational data, this association has been replicated in different populations and a compelling argument for a causative role PPIs comes from cases in which the hypomagnesaemia responds to PPI withdrawal and re-challenge. (Interestingly in these reports, hypomagnesaemia resolved surprisingly promptly - only a few days - after PPI withdrawal.)

What is the mechanism?

So what is the mechanism? Is it due to reduced intestinal absorption or increased renal excretion? We know that the kidney - and in particular the DCT - plays a crucial role in regulating Mg²⁺ homeostasis and that drugs that perturb renal Mg² handling can cause hypomagnesaemia. Mg²⁺ is re-absorbed through apical TRPM6 channels in DCT cells - and mutations in this channel cause hypomagnesaemia with secondary hypocalcaemia. This system is regulated by epidermal growth factor (EGF), which binds to basolateral receptors, stimulating TRPM6 activity.

Effect of anti-cancer therapies, diruretics and CNIs

In oncology, antibody and small-molecule inhibitors of EGF can promote renal Mg²⁺ loss for obvious reasons. Platinum-based agents - such as cisplatin - can induce profound and very long-lasting renal Mg²⁺ wasting. This is thought to be due to cisplatin accumulating within, and then killing, tubular cells.

Although the DCT is responsible for ‘fine-tuning’ renal Mg²⁺ excretion, the bulk of filtered Mg²⁺ is reabsorbed passively though a paracellular route in the PCT and TALH. Therefore loop diuretics - which diminish the driving force for this re-absorption - can also cause renal Mg²⁺ wasting. Tacrolimus can promote renal Mg²⁺ loss by reducing tubular TRPM6 expression via a calcineurin-dependent pathway.

Mechanism of PPI-induced hypomagnesaemia

PPIs, on the other hand, do not appear to promote renal Mg²⁺ wasting. In fact urinary Mg²⁺ excretion is appropriately reduced in cases of PPI-associated hypomagnesaemia. So the effect is presumably mediated through reduced intestinal absorption but the molecular mechanism has yet to be determined. The intestinal absorption of Mg²⁺ is predominantly through TRPM6 and TRPM7 channels. In heterologous expression systems, the activity of these channels is pH-dependent, with higher inward currents being observed under acid conditions. Therefore it seems plausible that PPIs, by promoting an alkaline intestinal environment, might reduce Mg²⁺ absorption.