Chloride: Queen of the Electrolytes

In June's edition of JASN Jacques et al. highlighted the emerging importance of the role of chloride in the pathogenesis of hypertension. Their group developed a mouse model that over expressed the protein pendrin in the aldosterone-sensitive region of the distal tubule. These mice developed hypertension that was attributed to increased NaCl absorption driven by over expression and increased activity of the pendrin chloride exchanger.

Pendrin was first described as a chloride channel in the kidney in the early 2000s. Pendrin is a chloride-bicarbonate exchange protein that facilitates the electroneutral movement of chloride to the intracellular space and bicarbonate to the extracellular space or urinary space. This channel is also found in the thyroid and inner ear and is the gene that causes Pendreds syndrom.

It is now widely accepted that the pressor effects of salt (NaCl) are dependent on Na as the major determinant of intravascular volume and thus hypertension. It has also been demonstrated that for Na to mediate a hypertensive effect, it needs to be in the form of NaCl (Berghoff and Geraci, Intern Med J 56:395-397). In their study, Berghoff and Geraci showed that subjects on a high NaCl diet but not on a high NaBicarbonate diet developed hypertension. These experiments have been reproduced in human and animal models. Interestingly, hypertensive and normotensive subjects switched from a NaCl diet to an equimolar NaBicarbonate diet experienced a decrease in blood pressure.

Pendrin is normally found in the type B Intercalated cells of the aldosterone region of the nephron. Recently published studies by the same group suggest that pendrin can also work in tandem with the Na-dependent chloride/bicarbonate exchanger (this is a different channel to pendrin and is also found in the CCD) resulting in electroneutral NaCl absorption and that this process is thiazide sensitive.

In JASNs June edition, the Jacques group showed that pendrin mediates chloride absorption distally and that this is the driving force for Na absorption distally either through the ENaC and/or Ndcbe channels. The significance of their findings are that 1) chloride is required for NaCl absorption in ‘salt sensitive’ hypertension and that 2) pendrin is the channel that facilitates the absorption of chloride.

On the basis of this paper and other papers showing similar findings with regard to Pendrin's role in NaCl balance the authors suggest their work solidifies the concept of chloride-sensitive hypertension.

It must be remembered that these studies don’t dispute that Na is primary in maintaining blood volume and driving hypertension. However, chloride absorption is a necessary requirement for the absorption of Na in the setting of a salt load causing hypertension. Thus, Chloride might be the queen and Na the king of extracellular solutes!

See these previous posts on Pendrin function in the kidney.

Posted by Andrew Malone

Electrolyte Channels and Aldosteronism

Over the past few years, it has become apparent that hyperaldosteronism is far commoner than was once suspected and screening of unselected patients with hypertension reveals that about 5-10% of patients have primary hyperaldosteronism. In patients with resistant hypertension, that percentage increases to 15-20%. About 30% of hyperaldosteronism is caused by aldosterone producing adrenal adenomas (APA). Most of the rest is related to bilateral adrenal hyperplasia with less than 5% of cases being familial. The secretion of aldosterone in adrenal cells is dependent on the intracellular calcium concentration and increases in response to higher plasma calcium. Entry of calcium into the cells is in turn dependent on voltage-gated membrane calcium channels (which allow calcium influx when the cells are depolarized) and a calcium ATPase which removes calcium from the cells. Under normal circumstances, adrenal cells are hyperpolarized thus keeping these calcium channels closed. Cell polarization is maintained by a combination of the action of the Na-K-ATPase (which exchanges 3 intracellular Na for 2 extracellular K) and membrane K channels lead to K loss from the cells.

Angiotensin II inhibits the Na-K-ATPase leading to cell depolarization, calcium influx into cells and aldosterone secretion. Similar effects are seen when cells are treated with oubain, a specific Na-K-ATPase inhibitor that also leads to hyperaldosteronism.

In 2011 in a seminal paper in Science, Choi et al reported finding somatic mutations in KCNJ5, a membrane potassium channel in patients with APA. These were identified by sequencing tissue from the tumors and comparing with the surrounding tissue. Subsequently, it has been found that about 30-40% of patients with APA have somatic mutations in KCNJ5. These mutations are believed to reduce the ion selectivity of the channels, allowing Na to move into the cell and reduce the resting membrane potential. A number of families have been identified with KCNJ5 mutations resulting in bilateral hyperplasia - now called Familial Hyperaldosteronism type III.

Recently, a paper was published in Nature Genetics which attempted to determine if there were other somatic mutations in patients with APA. In this study, they took KCNJ5-normal patients and sequenced the exons of the tumors and the surrounding tissue. There were very few mutations identified but 5/9 patients had mutations in ATP1A1, a component of the Na-K-ATPase or ATP2B3, a component of the calcium ATPase that removes calcium from adrenal cells. Follow-up targeted sequencing of 300 patients with APA revealed that about 7% had mutations in one of these two genes. Patients with these mutations had higher aldosterone levels, lower minimum potassium levels and higher systolic BP, all indicators of more severe disease. Notably, no families have been identified with these mutations. In vitro studies revealed that cells with these mutations have very low membrane potentials and it is speculated that if this was a germline mutation, it would likely not be compatible with life. This is a fascinating insight into how very small changes in electrolyte channels can have far-reaching consequences and shows a great progression from exome sequencing to the bench and to clinical investigation.

The images in this post are taken from the recent paper in Nature Genetics. One would wonder if somatic mutations explain some of the missing heritability that were are seeing in genetic studies of common diseases. See this previous post by Lisa on the genetic causes of hypertension.

Which thiazide? - the debate continues

The debate about which thiazide diuretic to prescribe patients with hypertension has been going on for years without resolution and both HCTZ and chlorthalidone have their supporters. This topic has been discussed in the past on the blog with the general sense being the chlorthalidone may be better although the objective evidence was not very strong. Unfortunately, the trial that would answer this for good: an RCT of chlorthalidone vs. HCTZ, will never be done so we have to depend on observational trials, imperfect as they may be, to try and get the answer. The argument in favor of chlorthalidone relies on the longer half-life of the drug which allows once-daily dosing with 24 hour blood pressure control.

An article in Annals of Internal Medicine gives us a little more information to help make an informed decision. The authors reviewed the records of 10000 patients in Ontario treated with chlorthalidone between 1993 and 2010. These were matched using a propensity score to 19000 patients treated with HCTZ and all were followed for a maximum of 5 years. All patients were over the age of 66 at the time of starting the diuretic and patients who had a major CV event in the year prior to entry into the study were excluded. The primary outcome was CV death or a major CV event. The authors believed that they were going to demonstrate a significant benefit for chlorthalidone. The overall results of the study are shown below:

There was no difference in the primary outcome between the two groups. In a safety analysis, the use of chlorthalidone was associated with a threefold higher OR for admission with hypokalemia and almost double the OR for admission with hyponatremia. There was no difference in the risk of all-cause hospitalization. The dose of chlorthalidone available on the formulary in Canada is 50mg daily so the thought was that this difference may be related to the use of higher doses but a post-hoc analysis showed that, irrespective of the dose used, chlorthalidone was associated with a higher risk of hypokalemia and hyponatremia. Looking back, this makes sense. The half-life of chlorthalidone is so much longer than HCTZ that potassium wasting is almost guaranteed. In fact, it has been shown in the past that chlorthalidone causes potassium wasting at much lower doses than HCTZ. Technically, HCTZ should be given twice daily because of the short half-life but it generally is not. I wonder if it was, would you see the same effect on electrolyte concentrations?

There is (as always) a caveat. There may have been some unmeasured confounding. It is uncertain why some physicians may have chosen chlorthalidone over HCTZ. The other formulation of chlorthalidone that is available in Canada is a combination drug with atenolol. As a result, the rates of use of B-blockers was higher in the chlorthalidone group and the rate of the use of ACEi was lower. This is a really interesting study. I have been tending to use more chlorthalidone in my practice over the last few years based on the limited that that were available but I am not sure what the correct answer is now. It should be noted that the UK guidelines now recommend thiazides as a 3rd line therapy for hypertension following CCBs and ACEi.

This is a great interview with the first author of the paper on Medscape which is worth reading.

Electrolyte Disorders involving Tubular Channels

Though adult nephrologists infrequently encounter these disorders in clinic, the Board Exam loves them. Below a short table describing some of these gain- and loss-of-function channel disorders that are worth remembering. The diuretic-targeted channels are shown under parenthesis as a reference.

Combo

Azilsartan medoxomil is a relatively new angiotensin receptor blocker and a study was recently published in Hypertension which compared the combination of two different doses of this drug with chlorthalidone against olmesartan in combination with hydrochlorothiazide for the treatment of stage II hypertension. Both combinations were effective at treating hypertension although the reduction in systolic blood pressures was significantly higher in both azilsartan medoxomil/chlorthalidone arms. There was very little difference between the higher and lower doses of azilsartan medoxomil in terms of effectiveness but there was a higher incidence of adverse effects (mostly dizziness/hypotension or an elevated creatinine) in the high dose group.

This begs the question whether the increased effectiveness of the new combination was due to the effect of the azilsartan medoxomil or the chlorthalidone. Chlorthalidone and hydrochlorothiazide have never been directly compared in a randomized trial and this study is unlikely to ever be done because it simply is not cost effective. However, there is a growing consensus that chlorthalidone is the more effective drug for the treatment of hypertension and prevention of secondary events. Add this to the fact that the majority of patients are on suboptimal doses of hydrochlorothiazide and there is an argument that we should be starting patients primarily on chlorthalidone (if not switching existing patients). To give the authors of this paper their due, they did not gloss over this fact and included a paragraph in both the introduction and discussion about the relative effectiveness of chlorthalidone vs. hydrochlorothiazide and suggested that this could have contributed to the increased effectiveness of their combination drug.

I believe that we should always try to give patients as few tablets as possible and as a result, there is a certain logic to combinations of ARB/ACEi + thiazide diuretics. This is the first ACE/ARB that has been combined with chlorthalidone in a single pill and it may be an attractive option for that reason. See this review about the relative benefits of chlorthalidone vs. hydrochlorothiazide (although these authors did not think that the evidence was sufficient to argue convincingly for one over the other), and this previous post by Lisa about the relative efffectiveness of the two drugs.

It's a pity that this study was not done as a direct comparison of two ARBs in combination with chlorthalidone as it would have been easier to judge the relative merits of the drugs without this significant confounding factor.

Under Pressure

As a medical student I was taught the CKD hypertension gospel straight from the good book of JNC VII: Thou shalt lower the blood pressure to less than 130/80! This was many years after David Bowe and Freddie Mercury but I got the song stuck in my head when I started thinking about the post so I had to put it up there.

I lived happily with this for many years until one day someone questioned me. Why should you lower the blood pressure to less than 130/80 in someone with chronic kidney disease? Well 'cause the JNC VII says so! Check it out...


Right there in red, blue and black. And supported by two references no less! One of them is the American Diabetic Association going on about diabetes (another story) but reference 21 is KDOQI on CKD... So the rabbit hole gets deeper.

Over at KDOQI we get the following...


They say "controlled trials in essential hypertension conclusively show a beneficial effect of lowering blood pressure to <140/90 mm Hg. Controlled trials in high-risk individuals with diabetes or heart failure suggest beneficial effects of reduction of blood pressure to even lower values. Based on these studies, and on observational studies, a number of guidelines for patients with either diabetes mellitus or congestive heart failure recommend a goal blood pressure of <130/80 mm Hg. There are few studies regarding blood pressure goals for CVD risk reduction in patients with CKD. Thus, the Work Group elected to extrapolate the recommendations for high-risk patients to patients with CKD."

Uhh so, we have no evidence so we took some evidence from other diseases and said do the same thing. It not quite that bad. There is some evidence for less than 130/80 but it has caveats.

The MDRD study randomized patients to aggressive vs standard blood pressure control with achieved average values of 126/77 and 133/80 respectively. At the end of the study there was no overall difference between the two groups in terms of kidney function but in post-hoc analysis the aggressive BP arm had statistically slower rates of renal function decline in patients with over 1g per day of proteinuria mainly driven by patients with over 3g of proteinuria per day. Unfortunately, the aggressive control group were more likely to have received ACE inhibitors than the standard control group so the post-hoc data is a bit muddled.

In the recently published long term followup of the AASK trial, African Americans with hypertensive kidney disease who were initially randomized to either intensive or standard BP control were subsequently followed in a cohort phase in which the BP target was the same in both groups. Followup extended out to 12 years from the initial randomization. The achieved BPs during the trial were 130/78 mm Hg vs 141/86 mm in the intensive and standard groups respectively. In the cohort phase BPs were much closer as expected (131/78 and 134/78 in the intensive and standard groups respectively).

The story is similar to MDRD, among all patients there was no difference in the primary composite outcome of ESRD, doubling of serum creatinine or death throughout the trial and cohort phase. However, in the subgroup with baseline proteinuria of greater than 220 mg per day a significant difference between BP target groups appeared favoring more intensive control.


So no clean randomized prospective data to support the JNC VII target of less than 130/80 in CKD patients. There is a hint from the above subgroup analyses that CKD patients with proteinuria might benefit from having blood pressures controlled to below 130/80. The proteinuria cutpoint at which this might occur is unclear.

It will be interesting to see how JNC VIII, expected sometime later this year, handles the above. Additional information will hopefully come from the randomized prospective SPRINT trial which is looking at systolic BP goals of 140 vs 120 in a large cohort with a reasonable proportion of CKD patients.