Mg & K

It is well known that hypokalemia does not correct easily if it is accompanied by hypomagnesemia. A medical student I met looked into this topic and found a “Science in Renal Medicine” article. According to this article, one of the mechanisms through which hypokalemia occurs in a hypomagnesemic state is through renal potassium wasting. Several observations have shown that magnesium infusion decreases renal K secretion in the distal nephron.

A study from Nature found that ROMK (aka Kir), one of two potassium channels in the distal nephron, is responsible for the distal renal K wasting in hypomagnesemia. The mechanism is that the intra-cellular free Mg blocks the pore of the ROMK channel and limits potassium secretion in a concentration-dependent manner; therefore low intracellular Mg level increases potassium secretion.

Some renal Mg wasting disorders (e.g. Mg channel TRPM6 mutation) do not always present with hypokalemia. Why is that? The reason is that you need 2 components for potassium excretion. One is increased K permeability of the ROMK, and the other is a driving force to secrete K like increased distal Na delivery or an elevated aldosterone level (via enhanced Na reabsorption in the distal nephron). It seems in these disorders you don’t have the second determinant for K secretion.

Another fascinating renal physiology article! Now we are still confused but have a better understanding of hypomagnesemia in a case of hypokalemia. 

Posted by Tomoki Tsukahara

PPI-Associated Hypomagnesemia

At renal grand rounds today, we heard about a case of severe hypomagnesemia in a patient who was on chronic omeprazole therapy. While the etiology of the low Mg2+ was likely multifactorial, I was surprised to find out that the PPI could have played a causal role. To date, there have been several case series of patients with profound hypomagnesemia that appeared to be due to PPI treatment. The most recent came from Hoorn et al, in which four patients with PPI-induced hypomagnesemia were described. All four had been on PPI therapy for at least one year, and serum Mg2+ ranged from 0.16 to 0.68 mEq/L before repletion. Hypomagnesemia resolved as early as two weeks after discontinuation of the PPI in one case, and took up to three months in another patient. Concomitant hypokalemia was also present in all four cases, and normalized with correction of the serum magnesium.

The mechanism of PPI-induced hypomagnesemia is unclear, although it is hypothesized that somehow the drugs interfere with gastrointestinal absorption. However, data from one case report suggest that a renal effect may also contribute. Regolisti et al described a patient with hypomagnesemia while on pantoprazole. An intravenous infusion of magnesium was used to determine the kidney’s maximum tubular magnesium reabsorption threshold, or the serum ultrafilterable magnesium concentration below which the kidneys retain most of the filtered magnesium. The serum and urine Mg were measured during a period of IV Mg infusion, and the point at which the urine Mg began to increase was deemed the point at which the renal tubular mechanisms for Mg reabsorption were overwhelmed. The maximum tubular reabsorption threshold for Mg was markedly less (0.90 mEq/L) in the patient compared to normal persons (≥ 1.20 mEq/L).

Although the incidence of PPI-induced refractory hypomagnesemia is assuredly quite low, given the infrequent case reports and the large number of people taking PPIs, it should be considered on the differential diagnosis of hypoMg (see Nate’s post) in any patient on a PPI whose low magnesium level is proving hard to correct.

An excursion into Magnesium homeostasis

Magnesium (Mg++) is a predominantly intracellular divalent cation which is critical for many metabolic processes and participates in >300 enzymatic reactions. It is essential for many critical transporters including the Sodium/Potassium ATPase cotransporter. Mg++ also has a critical role for DNA replication, transcription and translation.

Mg++ intracellular homeostasis is complex because it is compartmentalized in different organelles in the cell with different concentration.
The distribution of Mg++ in the human body is interesting.

• Serum 0.3%
  
• RBCs 0.5%
• Soft tissue 19.3%
• Muscle 27%
• Bone 52.9%
  

Therefore measuring serum Mg++ represents an inaccurate way to assess total body Mg++ stores and can be misleading. In addition, there is no standardized normal range for Mg++ and values vary from lab to lab. E.g., at the Brigham & Women's (1.8-2.5mg/dl), Mass General (1.4-2.0mg/dl) and VA (1.8-2.4 mg/dl) hospitals there is quite a discrepancy in what is considered a normal range.

Clinical signs of hypomagnesemia (from mild to severe) include loss of appetite, nausea/vomitting, fatigue, weakness, numbness, tingling, muscle contractions/cramps, seizures, nystagmus, personality changes, hypokalemia, hypocalcemia, arrhythmias and coronary spasms.

Causes of hypomagnesmia can be reduced intake and/or absorption e.g. in malabsorption syndromes, change in redistribution e.g. during exchange transfusions and last but not least reduced renal re-absorption which is the most likely etiology. Causes include alcoholism, diabetes mellitus, hyperthyroidism, hypercalcemia and several medications (loop diuretics, aminoglycosides, cisplatin, calcineurin inhibitors, etc.).

Approximately 75-80% of serum Mg++ is filtered in the glomerulus. 15-20% are re-absorbed in the PT, ~65-75% are re-absorbed in the TAL and 5-10% are re-absorbed in the DCT. The DCT is the site of fine regulation of Mg++ excretion. The fractional excretion of Mg++ can range from 0.5% to 80% but typically is in the range of 3-5%.

How Mg++ re-absorption is regulated in the kidney is still unclear. Compared to other electrolytes there was no hormonal or regulatory known until recently. Its re-absorption appeared to be coupled to Calcium re-absorption. However, rare inherited Mendelian forms of Mg++ disorders have given insight into the molecular mechanisms of abnormal Mg+ homestasis:

Condition: Gene Mode of inheritance tubular location Urine Ca excretion
FHHNC: Claudin16 AR TAL High
BARTTER’s: CLCNKB AR TAL High
ADH: CaSR AD TAL&DCT High
FHH: CaSR AD TAL&DCT Low
NSHPT: CaSR AR TAL&DCT Low
GS: NCCT AR DCT Low
HSH: TRPM6 AR DCT Low
IDH: NaK-ATPase AD DCT Low
Mitoch.: tRNAile Maternal lineage DCT Low

Abbreviations:

FHHNC = Familial hypomagnesemic hypercalciuria and nephrocalcinosis
AR = Autosomal recessive
AD = Autosomal dominant
ADH = Autosomal dominant hypocalcemia
FHH = Familial Hypercalcemia with hypocalciuria
NSHPT = Neonatal severe hyperparathyroidism
GS = Gitelman syndrome
HSH = Hypomagnesemia with secondary hypocalcemia
IDH = Isolated dominant hypomagnesemia
CaSR = Calcium-sensing receptor
NNCT = Sodium-Chloride Cotransporter
TRPM6 = transient receptor potenetial cation channel, subfamily M, member 6.

A few comments on these inherited diseases which may be relevant. FHH and NSHPT feature typically elevated serum Mg++ levels. Disorders of hypomagnesemia located to the DCT have typically low urine calcium excretion compared to disorders located to TAL which have hypercalciuria. Another difference based on location of defect in the tubulus is degree of "hypermagnesuria". TAL defects result typically in higher FeMg++ of 15-50%, whereas hypomagnesemia caused by defects in the DCT results in lower levels of FeMg++ (5-15%). Patients with mutation in the gene Claudin 19, a paracellular tight junction protein, have similar phenotype to FHHNC caused by Claudin 16 (Paracellin). It turns out that Claudin 16 and Claudin 19 form a channel like structure to transport Mg++ through paracellular pathway in the TAL. This may be the most important mechanism of Mg++ transport in the TAL.

An interesting new chapter on Mg++ homeostasis began in 2007 based on a report by Bindel and colleagues in JCI. They reported that the EGF receptor may regulate TRPM6, a Mg++ channel in the DCT and that EGF is a magnesiotropic hormone. They reached that conclusion by reporting a family with a recessive form of hypomagnesemia with a loss-of-function mutation in Pro-EGF, a precursor of EGF, leading to lower EGF levels. Further evidence for this mechanism was shown in patients treated with Cetuximab, an anti-EGF-receptor antibody which causes hypomagnesemia.

In summary, Mg++ deficiency is probably more prevalent than recognized since serum Mg++ may or may not reflect intracellular Mg++ stores. Hypomagnesemia is linked to human disease since patients with low serum Mg++ have poorer outcome. Mg++ homeostasis is still poorly understood, however inherited forms of hypo- and hypermagnesemia provide the best understanding of its regulation.

Revealed: my "covert" project with Nate a.k.a TRP channels in the kidney

Nate Hellman’s bench was three benches down from my lab. Nate and I trained together as clinical fellows. He and I had also brainstormed on research projects involving TRP channels and kidney disease. TRP channels are my research area of interest. It therefore seems appropriate to discuss some aspects of what Nate and I jokingly referred to as our “covert” project in my first blog posting.

What are TRP channels? And why do they matter in terms of kidney health and disease?

TRP stands for Transient Receptor Potential, a large family of non-selective cationic channels with diverse tissue distribution and diverse cellular functions. They were initially discovered in Drosophila (fruit fly) photoreceptors where they mediate fly vision. Some refer to them as “the last bastion of ion channels” since there is still much we do not understand about their role in health and disease. There are a few TRP subfamilies, indicated by letters which are there for various historical reasons (a discussion for another day – just take my word for it for now, or refer to a review by Ramsey et al., Annu Rev Physiol. 2006;68:619-47), but there are the TRPCs, the TRPVs, the TRPMs, the TRPPs, the TRPMLs and the TRPAs.

A few fun facts:
- TRP channels (TRPV1) are responsible for the hot taste of chili peppers in your mouth.
- TRP channels (TRPM8) also give you the cold sensation of menthol.

But how are TRP channels pertinent to your kidneys? It turns out that they are actually involved in many aspects of kidney physiology and disease (called “channelopathies”):

We’ll start from my favorite: Proteinuric kidney disease. Mutations in TRPC6 were found in a number of families with adult onset Focal Segmental Glomerulosclerosis. Many of us are now actively involved in research to identify the precise mechanisms by which disease occurs in these patients, but deleterious effects due to channel mutations in glomerular podocytes are strongly suspected.

Another channel, TRPV5, mediates vitamin D dependent calcium uptake in tubular epithelial cells. The absence of TRPV5 channels (at least in mice) causes renal calcium wasting and bone loss.

Perhaps more intriguingly, mutations in TRPM6 have been implicated in human hypomagnesemia with secondary hypocalcemia (HGH) as this channel is involved in renal magnesium uptake.

And rather famously, of course, polycystic kidney disease (ADPKD) emerges due to mutations in two slightly more distant relatives in the TRP family, the polycystins, known as TRPP1 and TRPP2.

This of course brings us full circle back to Nate and his research, which was focused on cystic disease, and specifically cystic kidney disease.

As this is my first time blogging, please let me know what you think, your comments and suggestions are welcome!

Differential Diagnosis of Hypomagnesemia

Why do we care about hypomagnesemia? And why are cardiologists so eager to replete the serum magnesium above 2.0 mg/dL?

Very low serum Mg can result in serious cardiovascular and CNS effects. Specifically, hypomagnesemia can cause QRS widening and may predispose to various arrhythmias (there is a nice section on this in Up-To-Date under "Significance of Hypomagnesemia in Cardiovascular Disease." Furthermore, very low serum Mg can result in CNS effects such as coma or seizure. In addition, hypomagnesemia is linked with two other important electrolyte abnormalities: hypokalemia (reflecting the clinical pearl that it is nearly impossible to correct total body potassium stores while the serum magnesium remains low) and hypocalcemia (which can result from hypomagnesemia-induced PTH resistance).

The following is one potential approach to hypomagnesemia:

1. Decreased Magnesium Intake: The big one here is chronic alcoholism, which is actually thought to be related both to a nutrititonal deficiency of Mg as well as a renal Mg wasting effect of EtOH.

2. Redistribution of Mg from the Extracellular to the Intracellular Space: This can occur as part of the constellation of electrolyte abnormalities seen with refeeding syndrome, hungry bone syndrome, or during the treatment of DKA.

3. GI Losses of Mg: This can result from nearly any cause of chronic diarrhea (e.g., Crohn’s Disease, hx small bowel resection, chronic infectious diarrheas, etc), as well as losses from vomiting or NG suction.

4. Renal Losses of Mg: Perhaps the most common cause of renal Mg wasting is simply diuretic use: both thiazide and loops diuretics can cause renal Mg loss. Other drugs (e.g., amphotericin B, aminoglycosides, cisplatin, pentamidine, cyclosporine, and tacrolimus) are also common culprits. Hypercalcemia also inhibits renal magnesium uptake. There are also a variety of genetic diseases that result in renal Mg loss, including Gitelman Syndrome, Bartter Syndrome, mutations in the paracellin or TRPM6 genes, and many others.

The Electrolyte Composition of the Dead Sea

The Dead Sea, located between Israel and Jordan, is considered one the saltiest bodies of water on earth, giving swimmers a peculiar buoyancy when immersed. Interestingly, the electrolyte composition of the Dead Sea is quite different from that of ordinary seawater. The salt composition of most ocean water is 97% sodium chloride, whereas the salt composition of the Dead Sea surface water is only 30.4% sodium chloride with additional contributions from calcium chloride (14.4%), potassium chloride (4.4%), and a shockingly high magnesium chloride (50.8%).

This latter point explains why near-drowning victims from the Dead Sea can exhibit profound elevations in the serum calcium and serum magnesium levels, which according to this article by Porath et al can reach levels up to 28.8 and 33 mg/dL, respectively! The authors make the case that early dialysis to rapidly lower serum calcium and magnesium levels is necessary to prevent the major electrophysiologic and hemodynamic consequences of hypercalcemia and hypermagnesemia. Interestingly, in this article and another by Oren et al, the authors point out that the presence of hypercalcemia in these patients is actually protective, in that high calcium levels help protect against the catastrophically high magnesium levels which might otherwise cause respiratory arrest in the setting of hypocalcemia.

Magnesium Therapy in Eclampsia/Pre-Eclampsia

Eclampsia and pre-eclampsia are characterized by the new onset of hypertension and proteinuria after 20 weeks of gestation in a previously normotensive woman. One of the major causes of morbidity to both mother & fetus is the occurrence of seizures. Fortunately, decades of experience with intravenous magnesium have led to a generally safe and effective use of this medication as an anticonvulsant. iv Mg is indicated both as a seizure prophylactic agent (in severe pre-eclampsia) as well as for the prevention of recurrent eclamptic seizures.

Generally, iv magnesium is given first as a loading dose (e.g., 6 grams iv bolus given over 15-20 minutes) followed by a continuous infusion of 2 grams per hour. An important caveat to be aware of as nephrologists is that as magnesium is excreted by the kidneys, individuals with acute or chronic renal failure are especially susceptible to hypermagnesemia and its toxic effects. This is not so uncommon, as thrombotic microangiopathy is often seen in women with advanced pre-eclampsia/eclampsia. Up-To-Date recommends giving the full loading dose (6 grams) but a reduced continuous infusion rate of 1gram per hour in individuals with moderately reduced GFR (Cr less than 2.5 mg/dL) and NO continuous infusion rate for individuals with a severely-reduced GFR (Cr greater than 2.5 mg/dL). Although the measured serum Mg concentration does not totally correlate with symptoms, the suggested therapeutic range is between 4.8 - 8.4 mg/dL.

Early magnesium toxicity can be detected as a loss of deep tendon reflexes (typically occuring at levels between 10-12 mg/dL) with more severe symptoms (respiratory paralysis, cardiac arrest) occuring at Mg levels greater than 12 mg/dL. Calcium gluconate can be given as a cardiac stabilizing agent in these instances. Mg therapy may also transiently suppress PTH release and can result in a mild hypocalcemia.

TRP Channels in Nephrology

The TRP (transient receptor potential) family of proteins is a group of related ion channels which is becoming increasingly relevant to the field of nephrologists. The TRPs are cation channels which are responsible for moving Ca2+ and Mg2+ ions across membranes; they were originally found in Drosophila and are named based on the fact that when light is shined on the fruit fly eye, instead of having a sustained photoreceptor response, there is only a transient response.

Examples of TRPs which have become important in Nephrology include:

-PKD2 (the 2nd most common disease gene for ADPKD, which is being renamed "TRPP2" based on the newest classification scheme for the TRP channels).

-TRPV5 & TRPV6 are expressed in the apical membrane of distal convoluted tubule cells and are felt to be responsible for calcium reabsorption at this site.

-TRPM6 mutations have been associated with hereditary hypomagnesemia.

-TRPC6 mutations have been found to cause a subset of familial nephrotic syndrome.

Why does hypomagnesemia result in refractory hypokalemia?

We've known this medical factoid since we were medical students: you can't successfully replete a potassium-depleted patient if they have low magnesium levels. But what is the mechanism by which this occurs?

One possible explanation is put forth in a 2007 JASN article by Huang and Kuo. In this paper, the authors suggest that magnesium regulates the activity of ROMK, the renal outer medullary potassium channel, providing a rationale for how low Mg levels lead to low K levels. ROMK is the inwardly rectifying K channel on the apical surface of the distal nephron which is required for the backleak of K+. When there is high intracellular Mg2+, it will block the ROMK channel pore and prevent K+ from effluxing. Conversely, a low intracellular Mg2+ would allow for high ROMK efflux activity and therefore result in K+ wasting. The authors are cautious to state that additional factors (e.g., high aldosterone levels, increased Na uptake, etc) may also be required to result in clinically significant renal K+ losses.

Hereditary Magnesium Wasting

There are a variety of interesting genetic diseases that can cause hereditary Magnesium wasting.

Renal magnesium handling is a little different than other ions in that the primary site of reabsorption is not the proximal convoluted tubule. Rather, the majority of Mg reabsorption occurs in the thick ascending limb (TAL). The key protein is termed paracellin, or claudin-16, which forms channels in the paracellular barrier which allows passage of the divalent cations Ca2+ and Mg2+. Thus, mutations in paracellin can result in both urinary Ca and urinary Mg wasting.

Ca2+ & Mg2+ reabsorption via the paracellular route is also linked to Na reabsorption. Recall that the Na/K/2Cl loop-sensitive Na channel is responsible for Na reabsorption in the TAL; although this is an electroneutral transporter, the backleak of K via ROMK channels creates a positive lumenal potential that drives Ca2+ and Mg2+ paracellular transport. This is why addition of a loop diuretic can lead to Ca2+ and Mg2+ wasting in the urine.

Some Mg reabsorption also takes place in the distal convoluted tubule (DCT) via a transcellular transport mechanism in which Mg is taken up via an apical Mg channel called TRPM6. It has recently been determined that epidermal growth factor receptor (EGFR) signaling is required for proper trafficking of TRPM6. Mutations in TRPM6 (causing the genetic disorder "hypomagnesemia with secondary hypocalcemia") as well as mutations in EGF can both therefore lead to urinary magnesium wasting.

Gitelman's Syndrome (caused by mutations in the thiazide-sensitive Na channel in the distal convoluted tubule) also results in chronic renal Mg wasting. Finally, an autosomal dominant-inherited dominant negative mutation in the Na-K ATPase also mysteriously results in isolated Mg wasting.

By the way, the image above (entitled "Magnesium Dice") is from an electron micrograph of some magnesium oxide crystals.