Hypokalemic Periodic Paralysis

A recent renal consult I encountered was a Cantonese gentleman with a classical symptomatic history for Hypokalemic Periodic Paralysis (HPP). He presented with a serum K of 1.4 mmol/l and profound weakness. Initially beginning in his teenage years, he had intermittent attacks of weakness lasting hours and affecting proximal muscle groups. Emergency department admissions invariably revealed low serum K.

Many of us will know the classical features to look for in the history:

• High risk Asian and Hispanic population groups, particularly males less than 20 years old.
• High carbohydrate meals triggering insulin release or  B-adrenergic surge from exercise or volume depletion.
• Thyrotoxicosis: A major subgroup of patients, usually men. The mechanism is thought to involve a combination of up regulation of Na-K-ATPase, loss of function of the inward potassium rectifying channel Kir2.6, and a feed forward effect in certain variants of the sulphonylurea receptor 1, culminating in dramatic intracellular potassium shifts. It is important to note is that rarely the paralytic episodes can predate the thyroid disease by many years.

The genetics of hypokalemic periodic paralysis have been discussed previously on Renal Fellow Network.

Management: More Questions than Answers

Acute management is relativity straightforward – administration of K, either IV or orally. Case control series demonstrate up to 70% of patients having rebound hyperkalemia of >5mmol/l if  KCl doses of over 90mmol/ are administered. Lower doses may potentially be used if concomitant B-blockade is deployed in conjunction. Oral KCl rescue is more suitable for home use.  As a rule of thumb, 40 to 60 mmol/l of oral  K⁺ raises plasma potassium concentration by 1.0 to 1.5 mmol/L, and 135 to 160 mmol/l K⁺ raises plasma potassium by 2.5 to 3.5 mmol/l.

Besides avoiding obvious environmental triggers, therapeutic interventions and prophylaxis are more unclear. Patients have normal total body potassium with no chronic GI or renal loss, thus the drop in serum levels is mediated via a transcellular shift. Despite this, prophylactic K supplementation remains a traditional cornerstone of therapy, although one would imagine a normally functioning cortical collecting duct should excrete this quite rapidly, particularly with chronic dosing regimens.

The “highest quality” of evidence comes from a Cochrane review of 3 very small studies, the largest examining the utility of dichlorphenamide, a carbonic anhydrase inhibitor, in 34 patients. Self-reported quality of life improved in 15 patients, and attack frequency dropped. This is in line with a more recent study in 2011 which quote a 50% improvement in symptoms in a larger group of patients on dichlorphenamide. This is unusual as the additional HCO3 in the collecting duct should increase intraluminal negative charge, and encourage potassium excretion, as should the volume depletion and increased RAAS activity. Furthermore, volume depletion could theoretically induce increase sympathetic output, worsening K loss. The most plausible explanation I found was a paper from 1975 suggesting the metabolic acidosis induced by the carbonic anhydrase inhibitor buffers the transcellular shift of K+.

Despite aldosterone levels being normal during attacks, reports suggest aldosterone antagonists may benefit patients as a second line therapy via their K+ retaining effects, although their action appears to be opposite to that of dichlorphenamide. It is curious these agents with supposed diametric effects on renal K handling both have positive effects on K balance in HPP.

The most intuitive treatment is B-blockade, demonstrated in a number of series to be effective, but almost always in those whose HPP occurs in association with thyrotoxicosis.

Authored by Eoin O'Sullivan

Could this be Refeeding Syndrome?

A young patient who was engaging in heavy weightlifting presented to the ED with proximal muscle weakness. The night before he had one hour of acute onset bilateral leg and hip flexor cramps with stiffness and "hardened" muscles and marked weakness that prevented him from standing or walking. This resolved spontaneously. After an intense workout the next morning he noted cramping and weakness in his legs and was unable to walk, therefore he presented to the ED. 

He had been taking a thyroid supplement for several months but had stopped about three weeks prior. He was also taking lisinopril for hypertension. He was currently using a steroid supplement containing designer steroids (10 mg androstenone and 10 mg androstan-one-azine) for several months. He also took vitamin B5 and niacin. He was eating a high protein diet mainly consisting of chicken and sauce (some sort of Teriyaki sauce) and some rice and very few vegetables for several months averaging 4000 to 8000 calories on most of the days of the week.

Two days before presentation he started eating "normally" again with high amounts of carbohydrates as a treat (cake and sweets).

In the ED: K 2.0 mmol/L, PO4 1.0 mg/dl, glucose 197 mg/dl, Mg 2.0 meq/L, CK 5070 U/L, TSH 0.01, low normal total T3, low total T4 and low free T4 but normal free T3. Urine electrolytes at the time of presentation were notable for a potassium of < 10 and an undetectable phosphorus level (Fractional excretion Phos < 5%). His ECG showed slight abnormalities but troponins were negative x 3.

Phosphate was repleted with 12 mmol NaPhosphate and normalized. Potassium was repleted with 40 meq KCl IV and 120 meq po until normal. His leg weakness resolved and the CK started to trend down.

The question is: what caused his profound electrolyte abnormalities? 

One possibility is refeeding syndrome as described in a previous post. The sudden surge of carbohydrates following a long period of high protein, low carb diet might have caused an increase in insulin driving potassium and phosphate into the cells. Hypomagnesemia was, however, not present in this patient. The time frame (within 4 days) would be consistent with refeeding syndrome. The rhabdomyolysis occurred as a consequence of hypokalemia and hypophosphatemia with a contribution from heavy exercise. He responded quite fast to potassium and phosphate supplementation and improved clinically within a day.

Patients with the following conditions have traditionally been at risk for refeeding syndrome: anorexia, chronic malnutrition (e.g. in patients with cancer), alcoholism, prolonged fasting, after a duodenal switch operation for obesity, hunger strikers and postoperative states. In these times of extreme dieting one should think outside the box and ask about special diets such as high protein diets. The kidney on the other side has been doing it's duty and preserved whatever electrolytes were still in the circulation by absolutely minimizing excretion of potassium and  and phosphate.
Posted by Florian Toegel

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 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.

Spare the Chloride

Fluid therapy is essential in ICUs and not surprisingly there is still much controversy about which fluid to use, how much and when. Nephrologists often roll their eyes at other subspecialty's preferences, e.g. surgeon's preferences for Ringers, citing the risk of hyperkalemia in renal failure patients given Ringers. I learned that normal saline is the preferred agent unless there is a special consideration such as acidemia necessitating alternatives. Now chloride, the partner of sodium that gets considerably less attention most of the time, enters the stage.

Yunos et al in JAMA suggest that too much of chloride increases acute kidney injury (AKI) episodes in tertiary ICUs and increases the need for renal replacement therapy (RRT) but does not affect mortality.

The physiological rationale for the detrimental effect of chloride on the kidney is described as vasoconstriction mediated by chloride in dog experiments and a possible role of tubuloglomerular feedback mediated vasoconstriction as well as decrease in GFR caused by increased distal chloride delivery. Furthermore they cite thromboxane mediated vasoconstriction caused by chloride and enhanced responsiveness to vasoconstrictor agents as possible physiological sequelae of chloride administration.

The authors of the JAMA article conducted a prospective, open-label sequential pilot study of patients admitted consecutively to the ICU. Initially patients were treated with chloride-rich IV fluids (0.9% saline, 4% succinylated gelatin solution or 4% albumin solution) and after that initial control period a chloride-restricted strategy was implemented with lactate (Hartmann solution), a balanced solution (Plasma-lyte 148) or chloride-poor 20% albumin as preferred agents.

The results were a lower increase in serum creatinine levels and fewer episodes of RRT in the chloride-restricted group but no differences in mortality, hospital or ICU length of stay or need for RRT after discharge.

How does this study affect our choice of ICU fluids? Certainly, these results are hypothesis generating and important but need to be viewed as preliminary given the design of the study. An accompanying editorial by Waikar mentions the Hawthorne effect as potential major concern. Clearly these important preliminary data need follow up in a controlled prospective trial. 

Posted by Florian Toegel

There's no such thing as a contraction alkalosis

We recently discussed an excellent paper on the classification of metabolic alkalosis. The three suggested subtypes were primary and secondary stimulation of collecting duct ion transport and exogenous alkali administration. Another interesting editorial was just published in JASN that further expands on the idea that chloride deficiency is central to the maintenance of a metabolic alkalosis.

The traditional view of a contraction alkalosis was that in a volume depleted patient, there would be increased reabsorption of sodium in the proximal tubule. Because this sodium must be reabsorbed with an anion, bicarbonate was also reabsorbed in the proximal tubule along with this in preference to chloride, thus perpetuating the alkalosis. The first challenge to this viewpoint came in the 1960s when it was shown that a chloride deficient alkalosis generated by diuretics or gastric aspiration was corrected by treatment with NaCl or KCl but not with Na or K repletion without Cl. This did not however deal with the issue of volume depletion.

More recently, the authors of the editorial have shown that a chloride deficient alkalosis could be corrected in rats by infusion of a chloride containing solution despite ongoing volume depletion, while restoration of the ECF volume with albumin did not correct the acid-base abnormality. In fact, the urinary excretion of bicarbonate increased in the rats that received chloride while it fell further in those that received volume expansion with albumin alone.

Finally, they treated normal human subjects with a low chloride diet along with furosemide and Na and K supplementation. These subjects developed an alkalosis that was maintained for 5 days and corrected with oral KCl alone without any expansion of plasma volume. This elegantly demonstrated that volume is not the issue in these cases and that it truly is an effect of chloride depletion alone.

So what is the mechanism for the maintenance of the alkalosis? Previous posts have discussed the role of Pendrin, the HCO3-Cl exchanger in the collecting duct. The main stimuli for pendrin activation are decreased distal delivery of chloride and intracellular alkalosis. However, where there is little or no distal Cl delivery, it is not available to exchange with HCO3 and thus the alkalosis is maintained. This also helps explain the alkalosis induced by hypokalemia. Hypokalemia induces intracellular acidosis which inhibits HCO3 excretion by pendrin thus exacerbating the extracellular alkalosis.

Can we now finally get rid of the concept of a contraction alkalosis?

Sodium and seizures?

The development of acute hyponatraemia can have profound neurological consequences. After creation of an osmotic gradient between the intravascular compartment and the intracellular compartment, water must somehow gain access to the brain tissue.

This appears to be mediated, at least partially, by aquaporin 4, based on evidence from mouse knockout models. Those mice deficient in AQP4 had significantly less brain oedema compared to wild-type animals after the induction of acute hyponatraemia.

In very acute situations the brain does not have enough time to implement its adaptive response mechanisms (which involve loss of intracellular solutes and osmolytes), and so acute cellular oedema can occur. It is in this situation that acute neurological sequelae are more common.

What if a patient presents to the ED post-generalized seizure, and the labs come back with a serum sodium of 130mmol/L? Could this seizure be ascribed to hyponatraemia? It actually could - one potential explanation is that the patient may have a pre-existing brain lesion that is more susceptible to osmotic changes. The second potential mechanism lies with the downstream effects of the seizure itself. Following the seizure, skeletal muscle cells can take on substantial amounts of water. This in turn may result in a ‘rise’ in the serum sodium concentration, by up to 10-15mmol/L in some estimates (from one of Dr M. Halperin’s acid-base textbooks). Definitely something to keep in mind.