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

The potential danger in treating Hypothermia-induced Hypokalemia

The post from Veeraish earlier this week reminded me of this patient who demonstrated an important learning point regarding hypokalemia in hypothermic patients. A 75 year old woman was found unconscious in her unheated home with overnight temperatures of -1⁰C. On arrival at the Emergency Department, her core rectal temperature was a staggering 21⁰C, blood pressure 90/50 and pulse was 28 beats per minute. EKG was classic, demonstrating slow atrial fibrillation, wide T wave inversion and the characteristic J waves of hypothermia (see Figure; note that the depth of the J wave inflection correlates with the degree of hypothermia). Laboratory values included  serum potassium of 1.1 mmol/L, phosphorous <1 mg/dl, pH 6.95, lactate 8.5 mmol/L, glucose 522 mg/dl. Her renal function was normal. After some initial warming, repeat potassium was 1.6 mmol/L and her heart rate improved. When she had been warmed to 26⁰C, the serum potassium corrected to 5.1 mmol/L before settling at 3.6 mmol/L (with no potassium supplementation). Her serum phosphorous level and blood sugars normalized when her body temperature rose above 30⁰C. She also spontaneously converted to sinus rhythm. 

This case illustrates the profound metabolic complications which can arise in the context of extreme hypothermia. Hypokalemia is well recognized in hypothermia, however, the drop in serum potassium levels is usually mild. Most reported cases involve intentional body cooling in treatment of severe head injury or post-cardiac arrest. The mechanism of hypokalemia is thought to be redistribution of potassium back into the cell. As mentioned by Veeraish, a case has been bravely described of a patient developing hypothermia-associated hypokalemia while being intentionally cooled after head injury. Treatment with potassium supplementation and re-warming occurred concurrently and the patient then suffered a fatal arrhythmia. As the serum potassium will correct itself with rewarming, we should be extremely cautious about administering potassium to hypothermic patients due to the risk of severe rebound hyperkalemia.

Hypothermia Protocol and Dialysis

I recently received an inpatient consultation to see a CKD 5D patient. The reason for consult, as is mostly the case with dialysis patients was that he “needs hemodialysis”.

This dialysis patient wasn’t the average bear though. He had had a witnessed cardiac arrest, was treated by EMS, and defibrillated. He had a return of spontaneous circulation after being pulseless for 20 minutes. As soon as he got to the ER, he was initiated on our standard institutional therapeutic hypothermia protocol.  I was called in to dialyze him because (it wasn’t his usual day) the cardiologist wanted to perform a left heart cath on him the following day, and they “did not want dialysis to interfere with that schedule”. My clinical assessment did not reveal a severe degree of volume overload. He wasn’t hyperkalemic, and had only a mild degree of lactic acidosis that was nicely compensated by him being appropriately ventilated. Due to the concerns that I talk about below, I did not see an emergent reason to dialyze him.

I would like to focus on a few teaching points from a nephrologist’s perspective that I took away from this scenario:

1. Therapeutic hypothermia entails cooling post cardiac arrest patients to 32-34 degrees Celsius, ideally within 6 hours of a cardiac arrest.  Both intravascular and surface cooling methods are used. At my institution, the protocol involves administering up to 3 liters of 0.9% saline (which has been cooled to a temperature of 4 degrees Celsius), over an hour. This is complemented by cooling vests. Once target temperature is reached, the cooling phase is continued for 12-24 hours, after which the patient is rewarmed gradually at the rate of 0.5 degrees Celsius/hour.
2. Sub-physiological body temperatures expectedly have adverse effects. Hypothermia can hamper leukocyte function, increasing infection risk later. Cardiac effects include bradycardia and prolonged QT interval (both were present in this patient). Finally, for us nephrologists, here are some adverse effects and pertinent points that we need to keep in mind for such patients:
3. Hypothermia can cause hypokalemia via two different mechanisms. Low temperature causes a transcellular shift of potassium in to the intracellular compartment. This effect is possibly mediated by increased beta adrenergic and sympathetic activity. In fact, hypokalemia in the setting of hypothermia must be repleted extremely cautiously, if at all, given the risk of rebound hyperkalemia as potassium moves back out of the cells when the patient is rewarmed. This rebound hyperkalemia can be frequently fatal due to arrhythmias.
4. The second mechanism by which hypothermia causes hypokalemia is by the induction of polyuria, also known as “cold diuresis”. This hypokalemia is mediated by increased urinary flow, and is seen in conjunction with hypovolemia, hypophosphatemia, and hypomagnesemia. I didn’t observe any of these in my patient, maybe because of his oligo-anuric status at baseline. Nevertheless, close monitoring of volume status and electrolytes is required.
5. Hypothermia interferes with platelet function and with the clotting cascade. In fact, as per this review, 22% of patients had bleeding post-hypothermia induction. That might be a concern when making the decision to dialyze post-hypothermia patients with heparin.
6. The other issue that I ran in to, that was specific to dialysis patients, was the concern about the patient’s temperature. As we know, most HD machines warm blood before returning in to the patient. With most machines, the warmer cannot actually be turned off and only goes as low as 35 degrees Celsius. In other words, dialysis can inadvertently warm the patient up to this temperature (from the target temp of 32 degrees, per the hypothermia protocol)! CRRT machines do have adjustable temp settings that goes down to 32 degrees, so that might be a safer alternative. Given the risk of inadvertently warming the patient, and because I did not see any emergent indication for dialysis, I did not dialyze the patient. I believed that in that situation, his hypothermia protocol took precedence over dialysis.

In my experience, I have observed that referring non-renal physicians often consider inpatient hemodialysis an ancillary service, akin to placing an order for an x-ray or a lab draw. Seasoned fellows have heard this phrase all too often, “I want you to come down and dialyze this patient”. You are then left with the unenviable task of explaining to the non-renal physician that the decision to dialyze would be made by the nephrologist after proper assessment of the patient (isn’t why they consulted you in the first place?). Let’s not allow our familiarity and comfort with dialysis technology lull us in to putting our guard down. Dialysis is an inherently intense and complicated procedure where multiple clinical parameters need to be closely watched. It’s a fact that is often lost in translation.

Posted by Veeraish Chauhan

Concept Map of Hypokalemia

Diabetic Nephropathy, or not?

A man in his 30s with a history of type 1 DM and chronic hypokalemia was referred to the renal clinic for investigation of CKD. His creatinine was 1.8g mg/dl.  His DM was well controlled without any evidence of retinopathy.  Urinalysis did not show any proteinuria or hematuria.  His renal biopsy showed focal tubular atrophy, dystrophic calcification in the scattered tubules, and did not have any signs of diabetic nephropathy.  His renal biopsy findings were therefore attributed to chronic hypokalemia.

Hypokalemia can cause kidney damage if it persists for longer than one month.   Chronic hypokalemia can cause non-specific vacuolar lesions in the epithelial vessels in the proximal tubules.  Typical renal biopsy will show interstitial nephritis, fibrosis, tubular atrophy and cyst formation.  The pathogenesis of hypokalemic nephropathy is not clear.  The hypotheses are:  1) complement activation and tubular cell damage by hypokalemia induced renal ammonium production 2) stimulation of cell growth and proliferation by intracellular acidosis 3) increased production of growth factors (VEGF, IGF-1) and cytokines by hypokalemia through an uncertain mechanism.

After further work-up, our patient was diagnosed with Giltelman syndrome.  He was started on potassium replacement and his Cr has remained stable since then.  

Posted by Jie Cui

Hypokalaemia induced polyuria

Last time we reviewed the proposed mechanisms by which hypercalcaemia can induce polyuria. It’s important to know that hypokalaemia can also precipitate this presentation. So here are the proposed mechanisms for this scenario.

Potassium is required for the thick ascending limb NaKCl2 co-transporter to operate. Remember that potassium is recycled via the apical ROMK channel, which facilitates ongoing sodium reabsorption in the TAL and maintenance of the medullary concentration gradient. Therefore, potassium deficiency may lead to concentrating defects via this pathway, leading to polyuria.

There is also some evidence that hypokalaemia leads to impaired responsiveness to ADH. The exact mechanism is unclear, but obviously decreased responsiveness to ADH may lead to large volumes of dilute urine.

Other interesting nuggets with hypokalaemia – movement of potassium out of cells in the proximal tubule (in the setting of hypokalaemia) is balanced by inward movement of hydrogen ions. The creation of an intracellular acidosis increases ammonia production by the proximal tubular cells, which may exacerbate problems in patients with decompensated liver disease.

Chronic potassium depletion (over a month at least) in humans can cause the development of vacuolar lesions in renal epithelial cells, primarily in the proximal tubule. If the deficiency persists over a longer time period, changes including interstitial nephritis, tubular atrophy and medullary cyst formation have been described. Potential mechanisms underlying these changes may be related to altered growth factor and cytokine production, or ammonia accumulation. This collection of findings has loosely been referred to as hypokalaemic nephropathy.

Hypokalemia and deafness

I attended a research seminar last week given by the discoverer of EAST syndrome. This a rare, autosomal recessive condition in which children present with Epilepsy, Ataxia, Sensorineural deafness and Tubulopathy. It was a fascinating lecture detailing the slow but painstaking process whereby they first realized that this was a unique condition and slowly, over time, discovered the cause. It is due to a defect in KCNJ10, a potassium channel expressed on the TAL, distal tubule and early collecting duct. It is thought that it allows potassium to escape the cell and hence is required for the proper function of the Na/K-ATPase. Affected patients present with hypokalemic metabolic alkalosis and salt-wasting. It is also expressed in the inner ear and the brain, particularly in the cerebellum, thus explaining the ataxia.

This made be wonder; how many other conditions exist where hypokalemia is associated with sensorineural deafness?

Antenatal Bartter syndrome with sensorineural deafness: This disease is due to a mutation in the gene BSND, which encodes for Barttin. Barttin is the beta subunit of the chloride channels ClCKA and ClCKB, expressed in the distal nephron and the inner ear. Affected children present with polyhydramnios, premature birth and severe neonatal salt-wasting. The deafness is progressive and irreversible. Unlike other forms of antenatal Bartter syndrome, it is not associated with nephrocalcinosis and does not respond to indomethacin. Although it often progresses to renal failure, this is not inevitable and milder phenotypes have been described.

Distal Renal Tubular Acidosis and Sensorineural Deafness: First described in 1966, this is an autosomal recessive disease caused by a mutation in the gene ATP6B1 leading to a defect in the H-ATPase. It is primarily expressed in the distal nephron but is also required for the maintenance of proper endolymph pH in the inner ear. Patients present with type 1 RTA, nephrocalcinosis, poor growth and irreversible sensorineural deafness.

Pendred Syndrome: This disease is thought to cause 10% of congenital deafness and was detailed in a previous post by Nate. It is due to a defect in HCO3-Cl exchange in the collecting duct. Affected patients are not usually hypokalemic under normal circumstances. However, they develop a hypokalemic metabolic alkalosis on treatment with thiazide diuretics, which is reversible on stopping the drug.

Mitochondrial Cytopathies: Sensorineural Deafness is a common problem in patients with mitochondrial disease and about 5% of patients have renal involvement; most commonly represented by the fanconi syndrome with RTA, hypokalemia, glucosuria and aminoaciduria presenting prior to 2 years of age. They can also be associated with glomerular disease and could be confused initially with Alport’s syndrome although hematuria is usually absent in these patients.

Honorable mention must go to loop diuretics, which along with causing hypokalemia, can lead to ototoxicity, particularly when used in high doses. They cause edema of the epithelium of the stria vascularis by changing ionic gradients between the perilymph and endolymph and the resulting hearing loss can be permanent.

Finally, there is a single case report from Japan of a patient who developed permanent unilateral sensorineural deafness following an episode of hypokalemic periodic paralysis. His potassium on presentation was 1.5 mmol/L and the deafness was thought to be due to an electrolyte imbalance in his inner ear.