A New Perspective on Hyperkalemia

Taipei Veterans General Hospital, Hsin-Chu branch

Director of Nephrology

Steve Chen

K

PotassiumPotassium

Reference Range:3.5 – 5.1 meq/L

PotassiumPotassium

Hyperkalemia is K+ > 5.5 meq/L

Pseudohyperkalemia Pseudohyperkalemia Poor phlebotomy technique:

fist clenching during phlebotomy raises both serum and plasma potassium by as much as 1 meq/L

Hemolysis : improper drawing blood Thrombocytosis ( > 500,000/µl)

Potassium is released from platelets during clotting, raising the serum but not plasma potassium platelet-induced serum pseudohyperkalemia

Leukocytosis   Leukemic lymphocytes are fragile and release potassium during centrifugation when exposed to high concentrations of heparin in the test tube ( reverse pseudohyperkalemia ) lymphocyte-induced plasma pseudohyperkalemia

Definitions of the severity of Definitions of the severity of hyperkalemiahyperkalemia

Author Year Mild Moderate Severe

Levinsky 1966 < 6.5 mmol/l

6.5–8 mmol/l with ECG : peaked T-waves

>8 mmol/l or any level + prolongation of the QRS complex/ventricular arrhythmias/heart block

Vanden Hoek et al.for American Heart Association

2005 5.1–5.9 mmol/l

6.0–6.9 mmol/l >7 mmol/l

Soar et al.for the European Resuscitation Council

2010 5.5–5.9 mmol/l

6.0–6.4 mmol/l ≥6.5 mmol/l

El-Sherif and Turitto

2011 5.5–7.5 mmol/l

7.5–10 mmol/l >10 mmol/l

Symptoms & Signs of Symptoms & Signs of Hyperkalemia Hyperkalemia

Clinical FeaturesClinical Features– CardiovascularCardiovascular

V-Fib, complete heart block, asystoleV-Fib, complete heart block, asystole EKG abnormalitiesEKG abnormalities

– Tall, peaked T-waves, short QT, prolonged PRTall, peaked T-waves, short QT, prolonged PR– QRS widening, flattening of P-waveQRS widening, flattening of P-wave– QRS complex degrades into sine wave patternQRS complex degrades into sine wave pattern

EKG findingsEKG findings Increased T-wave amplitude 6 to 7 meq/L

Prolonged PR interval

QRS widening 7 to 8 meq/L Loss of P wave

Sine wave pattern 8 to 9 meq/L

Ventricular fibrillation or a-systole > 9meq/L

EKGEKG

Symptoms & Signs of Symptoms & Signs of HyperkalemiaHyperkalemia

Clinical Features (Cont)Clinical Features (Cont)– NeuromuscularNeuromuscular

Weakness, paresthesiasWeakness, paresthesias Areflexia, ascending paralysisAreflexia, ascending paralysis

– GastrointestinalGastrointestinal Intestinal colicIntestinal colic DiarrheaDiarrhea

Hyperkalemia, extra-renalHyperkalemia, extra-renal

UK secretion > 200meq/DGI: only if UK excretion↓Redistribution:

Metabolic acidosis: nonorganic Hormones: insulin deficiency, β-blockers Necrosis or depolarization Hyperkalemic periodic paralysis

Trans-cellular shiftTrans-cellular shift

Hyperkalemia, renalHyperkalemia, renal Expected renal response:

UK excretion > 200meq/D; TTKG > 10 UK excretion < 200meq/D Renal

CCr < 25ml/min ↓ GFR CCr > 25ml/min ↓ Tubular secretion

Low flow rate in CCD if TTKG > 10: low osmoles or flow confirm with loop diuretic

Low K in secretion in CCD if TTKG < 5: aldosterone minus check response to 9αF

Trans-tubular K GradientTrans-tubular K Gradient

TTKG: to interpret urine K by adjusting ﹝ ﹞it for water reabsorption in renal medulla to reflect K in lumen of CCD﹝ ﹞

TTKG= Uk÷(Uosm/Posm) /Pk﹛ ﹜TTKG, physiological : 6 ～ 8

Hyperkalemia, tubular secretion Hyperkalemia, tubular secretion TTKG < 5 TTKG > 10 Decreased circulating volume

Response to Low protein diet 9a-fludrocortisone

TTKG >10 TTK<10 Primary/secondary Hypotension HTN Hypoaldosteronism High renin & Low renin& aldosterone aldosterone

Pseudohypoaldosteronism Gordon’s K sparing diuretics Cyclosporine Distal RTA

Loop diuretic testLoop diuretic test

Loop diuretic induces peak diuresis: 10ml/min

UK excretion>140μmeq/min

99αfludrocortisoneαfludrocortisone

Oral dose: 100μg2Hrs later If TTKG>10: hypoaldosteronism If TTKG<10: aldosterone minus

ENaC Chloride shunt

Aldosterone minusAldosterone minuslumen positive lumen positive

Slow Na reabsorption Fast Cl reabsorption

↓ECV ↑Renin Renal salt wasting

↑ECV or normal ↓Renin No renal salt wasting

Low aldosterone bioactivity Spirinolatone / ACEI / ARB Heparin / βblocker ↓ENaC Amiloride / Trimethoprim

Chloride ShuntGordon’s syndromeDrugs: CsADistal RTA

PseudoHypoAldosteronism: PseudoHypoAldosteronism: PHAPHA

Bonny et al, JASN 13: 2399-2414, 2002Bonny et al, JASN 13: 2399-2414, 2002

Clinical Gene Defects Type I: AR AD

Renal: salt wasting/hypo-Na Hyper-K Metabolic acidosis PAC↑/PRA↑Extra-renal: chest, GI, skin Renal : spontaneous remission

ENaCMineracorticoid receptor

Type II: AD ( Gordon syndrome )

Renal: HTN Hyper-K HCMA normal PAC; PRA↓

A: 1q31-q42 B: WNK4C: WNK1

Type III: Acquired (obstructive nephropathy; UTI; lead; amyloidosis)

GFR↓; Excessive salt lossHyper-KHCMAPAC↑/PRA↑Transient PHA

Main danger of hyperkalemiaMain danger of hyperkalemiaCardiac arrhythmiaCardiac arrhythmia

Onset Duration Calcium gluconate: 10%, 10 ～ 20cc as a bolus

Immediate < 5 min

30～ 60min

NaHCO3: 45 ～ 90meq

5～ 10 min 1～ 2 hours

Albuterol: 10 ～ 20mg inh, 10min

15 ～ 30 min 2～ 3 hours

Glucose/Insulin 15 ～ 30 min 3 ～ 4 hoursHD Immediate Several hoursK exchange resin 1～ 4 hours Few hours

Therapeutic principlesTherapeutic principlesWho to treat ?

Hospital admission is often recommended for patients with SK > 6 meq/L ; Interventions for any patient with SK >6.5 meq/L

To minimize membrane excitabilityTo shift potassium into cells

Skeletal muscle is the reservoir for more than 70% of body potassium

Promote potassium loss

Calcium gluconate IVCalcium gluconate IV Indications:

Cardiac irritability or SK > 7.5 meq/L 10ml of 10% calcium gluconate IV

as a bolus over 5 to 10 min Repeat it if no change in ECG is seen

after 5 to 10 min How it helps……? It protects the myocardium from toxicity to potassium but, there is concern about digoxin toxicity: an inhibitor of

Na-K ATPase, which increases intracellular calcium

Sodium bicarbonateSodium bicarbonate Uptake of K by skeletal muscle by favoring Na-

HCO3 cotransport and Na-H exchange, which, by increasing intracellular sodium, increases the activity of Na-K ATPase

HCO3 ceased to be a recommended intervention for acute hyperkalemia: studies showing that bicarbonate has little effect on the serum potassium concentration in stable hemodialysis patients, except for metabolic acidosis

HCO3 is a rational therapy to enhance potassium excretion in patients with intact kidney function

Insulin & glucose IVInsulin & glucose IV10 units of regular insulin in 50 ml of 50 %

dextrose (bolus) Initial bolus should be followed by

continuous infusion of 5% dextrose↓SK by about 1 meq/L within an hour

Infusion of RI at 20 U/H after a 6.6-U priming dose in a 70-kg healthy subject will rapidly raise insulin levels to approximately 500 μU/ml ( > 100 μU/ml ) with a near maximal kalemic effect But, to maintain euglycemia at these insulin levels, infusion of glucose at 40 g/H is required

Idealized plasma insulin levels after commonly used regimens in a patient with ESRD

  beta-2 agonist albuterol beta-2 agonist albuterol (also called salbutamol)(also called salbutamol)  

Inhalation/Nebulization/IV has been studied in stable hyperkalemic patients with end-stage renal disease.

SK falls by 0.3 ～ 0.6 meq /L within 30 minutes The doses via inhalation (the only formulation available

in the United States): 4 ～ 8 times those for the treatment of acute asthma

At high doses, albuterol may stimulate both beta-1 receptors, which can precipitate arrhythmias, and alpha-receptors, which cause K release from the liver and can transiently increase SK by >0.4 meq/L

Dialysate KDialysate K

predialysis plasma K dialysate K

>7.0 meq/L <2.0 meq/L

>5.5 2.0

Arrhythmia 2.5-3.0

On digitalis 2.5-3.0

Response of plasma potassium to potassium removal by dialysis

Change in PK at the end of a 3-hour dialysis against a zero potassium dialysate (blue ) and 2 hours after dialysis (red )

100 mmol of potassium removed ( 70-kg subject) at the end of dialysis (blue ) and 2 hours after dialysis (red )

Sodium polystyrene sulfonate Sodium polystyrene sulfonate (Kayexalate) (Kayexalate)Cation exchange resins: polymer

each gram eliminates 1 meq K Sodium polystyren sulphonate Promote exchange of Na for K in GI tract

25 to 50g with 100ml of 20% sorbitol

3 to 4 times a daySerious gastrointestinal complications:

fatal colonic perforation

PatiromerPatiromer Patiromer's (non-absorbable synthetic polymer ) active

groups are comprised of alpha-fluorocarboxylic acids that are paired with calcium ions rather than sodium: each gram eliminates 1 meq K

The acid groups are dissociated, allowing them to bind potassium↓, ammonium, and magnesium↓

It does not swell appreciably when exposed to water and it does not require a laxative to reach the distal colon

Patiromer was approved by the United States Food and Drug Administration in October 2015 and should be available in early 2016

Sodium zirconium Sodium zirconium cyclosilicate cyclosilicate (ZS-9)(ZS-9)

A crystal that is highly selective for K and ammonium ions through mechanisms that are very similar to those of naturally occurring ion channels

Na, Ca, and Mg are too small to form such stable bonds, making it thermodynamically unfavorable for them to be bound by the crystal

Because ZS-9 does not contain acid groups that dissociate, it binds potassium throughout the gastrointestinal tract  Effective in the management of acute hyperkalemia

AddisonAddison’’s disease: s disease: partialpartialGagnon et al, NDT 2001Gagnon et al, NDT 2001

Hyponatremia Hyperkalemia or Normokalemia Mild hyperchloremic acidosis ↓Plasma anion gap: circulating cationic

sunstance ↑BUN and ↑Cr: modest ↑Hct UK excretion > 200meq/D Uald excretion↑ CCD flow rate↑

Aldosterone-ENaC Depolarizes Aldosterone-ENaC Depolarizes ROMK in CCD ROMK in CCD

E Na C

ROMK

Na K ATP aseDepolarize

+

Aldosterone+

Na

KV2R

AquaporinH2O CaSR

CaSR

K conservationK conservation

H+/K+- ATPase via MCD L/I: 0mM/>60mM→active process PPI use: ↓H+/K+- ATPase: UK +NaHCO3 wasting

↓Delivery via CCD

Progesterone in renal collecting duct Progesterone in renal collecting duct not just a sex hormone anymorenot just a sex hormone anymore

Progesterone+

KH

PR bound progesterone

HKα2 mRNA