A comprehensive review of hyperkalemia for deep learners

1. A New Perspective
on Hyperkalemia
Taipei Veterans General Hospital, Hsin-Chu branch
Director of Nephrology
Steve Chen
K

2. PotassiumPotassium
Reference Range:
3.5 – 5.1 meq/L

3. PotassiumPotassium
Hyperkalemia is K+
> 5.5 meq/L

4. 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

6. 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

7. Symptoms & Signs of HyperkalemiaSymptoms & Signs of 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

8. 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

9. EKGEKG

10. Symptoms & Signs of HyperkalemiaSymptoms & Signs of Hyperkalemia
 Clinical Features (Cont)Clinical Features (Cont)
– NeuromuscularNeuromuscular
 Weakness, paresthesiasWeakness, paresthesias
 Areflexia, ascending paralysisAreflexia, ascending paralysis
– GastrointestinalGastrointestinal
 Intestinal colicIntestinal colic
 DiarrheaDiarrhea

13. Hyperkalemia, extra-renalHyperkalemia, extra-renal
UK secretion > 200meq/D
GI: only if UK excretion↓
Redistribution:
Metabolic acidosis: nonorganic
Hormones: insulin deficiency, β-blockers
Necrosis or depolarization
Hyperkalemic periodic paralysis

14. Trans-cellular shiftTrans-cellular shift

15. 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

16. 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

17. Hyperkalemia, tubular secretionHyperkalemia, 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

18. Loop diuretic testLoop diuretic test
Loop diuretic induces
peak diuresis: 10ml/min
UK excretion>140μmeq/min

19. 9αfludrocortisone9αfludrocortisone
Oral dose: 100μg
2Hrs later
If TTKG>10: hypoaldosteronism
If TTKG<10: aldosterone minus
 ENaC
 Chloride shunt

20. Aldosterone minusAldosterone minus
lumen positivelumen 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 Shunt
Gordon’s syndrome
Drugs: CsA
Distal RTA

21. PseudoHypoAldosteronism: PHAPseudoHypoAldosteronism: PHA
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
ENaC
Mineracorticoid receptor
Type II: AD
( Gordon syndrome )
Renal: HTN
Hyper-K
HCMA
normal PAC; PRA↓
A: 1q31-q42
B: WNK4
C: WNK1
Type III:
Acquired
(obstructive
nephropathy; UTI;
lead; amyloidosis)
GFR↓; Excessive salt loss
Hyper-K
HCMA
PAC↑/PRA↑
Transient PHA

23. Main danger of hyperkalemiaMain danger of hyperkalemia
Cardiac 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 hours
HD Immediate Several hours
K exchange resin
1 ～ 4 hours Few hours

24. Therapeutic principlesTherapeutic principles
Who 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 excitability
To shift potassium into cells
Skeletal muscle is the reservoir for
more than 70% of body potassium
Promote potassium loss

25. 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

26. 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

27. Insulin & glucose IVInsulin & glucose IV
10 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

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

29. beta-2 agonist albuterolbeta-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

30. 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

31. 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 )

33. Sodium polystyrene sulfonateSodium 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 day
Serious gastrointestinal complications:
fatal colonic perforation

34. 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

35. Sodium zirconiumSodium zirconium
cyclosilicatecyclosilicate (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

37. AddisonAddison’’s disease:s disease: partialpartial
Gagnon 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↑

38. Aldosterone-ENaC DepolarizesAldosterone-ENaC Depolarizes
ROMK in CCDROMK in CCD
E Na C
ROMK
Na K ATP ase
Depolarize
+
Aldosterone
+
Na
K
V2R
Aquaporin
H2O CaSR
CaSR

40. 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

41. Progesterone in renal collecting ductProgesterone in renal collecting duct
not just a sex hormone anymorenot just a sex hormone anymore
Progesterone
+
K
H
PR bound progesterone
HKα2 mRNA