Hyperkalemia, an update

Conﬂicts of interest
• ZS Pharma honorarium*
• Relypsa bought me breakfast*
• Astute speaker bureau
• Alexis honorarium
• Astellas travel honorarium
• Davita partner in multiple dialysis units and a vascular access center

66 year old white male
CC: cough and fever
Started on TMP-SMX 3 days ago
PMHx: CKD 3, DM2, Hypertension
140
5.7
110
21 1.4
18
124

CC: cough and fever
140
5.7
110
21 1.4
18
124
How would you manage the potassium
a. You call that hyperkalemia? Do nothing
b. Stop the ACEi/ARB and TMP-SMX
c. Some combination of IV calcium,  
nebulized albuterol, insulin and glucose
d. 30 grams oral kayexalate
e. answers b, c and d
http://bit.ly/HyperK

CC: cough and fever
140
5.7
110
21 1.4
18
124
a. You call that hyperka- 
lemia? Do nothing.

Fralick M, Macdonald EM, Gomes T, et al. Co-trimoxazole and
sudden death in patients receiving inhibitors of renin-angiotensin
system: population based study. BMJ. 2014;349:g6196.

Ontario residents
Age ≥ 66
On an ACE or ARB
Over 17 years 39,000
cases of sudden death
1,110 within 7 days of
being prescribed an
antibiotic

Amoxicillin
TMP-SMX
Cipro
Norfloxacin
Nitrofurantoin
1.0 1.0
1.8 (1.5-2.2)
1.7 (1.4-2.0)
0.8 (0.6-1.1)
0.9 (0.7-1.3)
1.4 (1.1-1.8)
1.3 (1.0-1.6)
0.7 (0.5-1.0)
0.6 (0.5-0.9)
7 Day
unadjusted adjusted
1.0 1.0
1.8 (1.5-2.1)
1.5 (1.3-1.7)
0.9 (0.7-1.1)
1.1 (0.9-1.3)
1.5 (1.3-1.8)
1.2 (1.0-1.4)
0.8 (0.7-1.1)
1.0 (0.8-1.3)
14 Day
unadjusted adjusted

3 deaths per 1,000 prescriptions
TMP-SMX, over age 65, on an ACEi or ARB

Antoniou T, Gomes T,
Juurlink DN. Arch Intern
Med. 2010;170:1045-9.
Risk of admission for hyperkalemia rises
7-fold for people* prescribed TMP-SMX
*Age ≥66, ACEi/ARB

dct
ccd
K +
3 Na+ 2 K+
ATPase
+
Principal cell

dct
ccd
K +
3 Na+ 2 K+
ATPase
+
Principal cell
S o d i u m f l o w s d o w n a
c h e m i c a l g r a d i e n t

dct
ccd
K +
3 Na+ 2 K+
ATPase
+
+–
+–
+–
Principal cell
G e n e r a t e s a n e g a t i v e
c h a rg e i n t h e t u b u l e

dct
ccd
K +
3 Na+ 2 K+
ATPase
+
+–
+–
+–
Principal cell
G e n e r a t e s a n e g a t i v e
c h a rg e i n t h e t u b u l e
P o t a s s i u m s e c re t i o n

dct
ccd
K +
3 Na+ 2 K+
ATPase
+
+–
+–
+–
Principal cell
A n y p ro c e s s t h a t b l o c k s
t h e e N a C c h a n n e l c a n
c a u s e h y p e r k a l e m i a
D r u g s
• Tr i a m t e re n e
• A m i l o r i d e
• Tr i m e t h o p r i m ( a b x )
D i s e a s e s
• Ty p e 1 RTA
( e l e c t ro g e n i c )
• P s e u d o h y p o a l d o -
s t e ro n i s m t y p e 1
STOP

But what if we ignore TMP/SMX…how dangerous is a potassium of 5.5 to 6.5?

Veterans
N=245,808
2,103,422 measurements of potassium
Einhorn LM. Arch Intern Med. 2009;169(12):1156-62.

Veterans
N=245,808
0
20,000
40,000
60,000
80,000
Hyperkalemia
21,352
44,907
5.5-6.0 ≥6.0

Veterans
N=245,808
0
20,000
40,000
60,000
80,000
Hyperkalemia
21,352
44,907
5.5-6.0 ≥6.0
Incidenceper1,000patientmonths
0.0
2.5
5.0
7.5
10.0
RAAS No RAAS
1.772.3
8.227.67
CKD No CKD

5,945 patients died within 1 day of a potassium
measurement, odds ratio of death based on potassium
OddsRatioofdeathin1day
0
10
20
30
40
No CKD CKD 3 CKD 4 CKD 5
8.0
11.6
19.5
31.6
2.3
5.75.4
10.3
1.31.01.11.0
K < 5.5 K 5.5-6.0 K ≥ 6.0
Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance
in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-62.

measurement, % deaths for K and CKD status%ofpotassiumwithadeathin24hours
0
10
K < 5.5 K 5.5-6.0 K ≥ 6.0
4.8%
1.8%
0.4%
8.6%
3.2%
0.3%
No CKD CKD

measurement, % deaths for K and CKD status%ofpotassiumwithadeathin24hours
0
10
K < 5.5 K 5.5-6.0 K ≥ 6.0
4.8%
1.8%
0.4%
8.6%
3.2%
0.3%
No CKD CKD
The odds of death increased with
severity of hyperkalemia; however,
the risk of death was greater in the
absence of CKD than in the presence
of CKD.

How about some prospective data?

64.3±12.1
Age
female male
Asian
Black/African American
WhiteWeight
potassium
<5.5
5.5-6.0
≥6.0
5.6
50%
35%
14%
eGFR
openlabeltreat
4.6
85.1±18.6
46.3±30.5
Kosiborod M, Rasmussen HS, Lavin P, et al. HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223-33.

p l a c e b o 1 . 2 5 & 2 . 5 g 5 & 1 0 g
AT R I A L F I B 0 0 1
AT R I A L F L U T T E R 0 1 0
B R A D Y C A R D I A 0 0 1
PA L P I TAT I O N S 0 0 1
S I N U S
TA C H Y C A R D I A
0 0 1
V E N T R I C U L A R
E X T R A S Y S T O L E
0 0 1

p l a c e b o 1 . 2 5 & 2 . 5 g 5 & 1 0 g
AT R I A L F I B 1 0 1
L E F T B B B 0 1 0
B R A D Y C A R D I A 0 0 1
C H F 1 0 0
C V D I S O R D E R 1 0 0
D I A S T O L I C
D Y S F U N C T I O N
0 0 1
L O N G Q T 0 0 1

65.0±9.1
Age
female
male
White
Weight
potassium 4.455.9
eGFR
4.6
85.1±18.6
35.4±16.2
5.17
K ≥ 5.5
openlabeltreat
blindedplacebo
Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer. N Engl J Med. 2015;372(3):211-21.

2 patients during the initial
treatment phase and 1 in the
patiromer group during the
randomized withdrawal phase
had ECG changes consistent
with hyperkalemia

How about some prospective data?
Disagreement between the retrospective
view from 30,000 feet and carefully
collected prospective data.

P o t a s s i u m 8 . 5 m m o l / L d u e t o r h a b d o m y o l y s i s

P o t a s s i u m o f 9 . 9 , h e m o l y z e d s p e c i m e n

CC: cough and fever
140
5.7
110
21 1.4
18
124
d. 30 grams oral  
kayexalate

1938
Food, Drug, and Cosmetic Act

1962
Kefauver, Harris Amendment

10 oliguric patients
Treated with Sorbitol,
SPS, or both.

Sorbitol aloneSPS in blue
Potassium(mmol/L)
3
4
5
6
7
8
Day 0 Day 5

32 patients
SPS 20-60 grams a day
23 oliguric
AKI
9 CKD
everyone was treated, no controls
30 patients treated between 1 and 6 days
2 treated for 35 and 280 days respectively

Numberofpatients
0
1
2
3
4
5
Change in Potassium (mmol/L)
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2+
potassium change in
the first 24 hours

Potassium(mmol/L)
4.00
4.25
4.50
4.75
5.00
Time (hours)
0 4 8 12
Placebo Phenol SPS Phenol SPS Sorbitol SPS
Serum potassium after single dose

Potassium(mmol/L)
4.00
4.25
4.50
4.75
5.00
Time (hours)
0 4 8 12
Placebo Phenol SPS Phenol SPS Sorbitol SPS
Serum potassium after single dose
patients are not hyperkalemic | N=6

Potassium 5.0-5.9 mmol/L
GFR < 40 mL/min
PlaceboSPS 30 g qD
Primary outcome: mean difference in potassium from
baseline to the day after the last dose of study drug
7 days 7 days

16 randomized  
to SPS
15 analyzed
K+ fell 1.25
4
11
17 randomized  
to placebo
16 analyzed
K+ fell 0.21
10
6
P=0.07
P<0.001
eukalemia

16 randomized  
to SPS
15 analyzed
K+ fell 1.25
1
14
17 randomized  
to placebo
16 analyzed
K+ fell 0.21
10
6
P=0.002
P<0.001

“increase in constipation, nausea, and
vomiting in patients receiving SPS and an
increased prevalence of diarrhea in the
placebo group.”

Five patients received kayexalate and
sorbitol enemas for hyperkalemia
Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and
experimental support for the hypothesis. Surgery. 1987;101(3):267-72.

Five patients received kayexalate and
sorbitol enemas for hyperkalemia
all five of them developed colonic
necrosis and four died
Lillemoe KD, Romolo JL, Hamilton SR, Pennington LR, Burdick JF, Williams GM. Intestinal necrosis due to sodium polystyrene (Kayexalate) in sorbitol enemas: clinical and
experimental support for the hypothesis. Surgery. 1987;101(3):267-72.

Harel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Gastrointestinal adverse events with sodium
polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med. 2013;126(3):264.e9-24.

23 case reports
30 articles
7 case series
58 cases

23 case reports
30 articles
7 case series
58 cases
0
10
20
30
40
Before 1990 1990-2000 After 2000
31
24
3

23 case reports
30 articles
7 case series
58 cases
0
10
20
30
40
Before 1990 1990-2000 After 2000
31
24
3
mean age 58 years

23 case reports
30 articles
7 case series
58 cases
0
10
20
30
40
Before 1990 1990-2000 After 2000
31
24
3
women
men
mean age 58 years

23 case reports
30 articles
7 case series
58 cases
0
10
20
30
40
Before 1990 1990-2000 After 2000
31
24
3
women
men
mean age 58 years
No CKD
ESRD
CKD

23 case reports
30 articles
7 case series
58 cases
0
10
20
30
40
Before 1990 1990-2000 After 2000
31
24
3
women
men
mean age 58 years
No CKD
ESRD
CKD
Chronic
Acute

23 case reports
30 articles
7 case series
58 cases
0
10
20
30
40
Before 1990 1990-2000 After 2000
31
24
3
women
men
mean age 58 years
No CKD
ESRD
CKD
Chronic
Acute
SPS
SPS+Sorbitol

23 case reports
30 articles
7 case series
58 cases
0
10
20
30
40
Before 1990 1990-2000 After 2000
31
24
3
women
men
mean age 58 years
No CKD
ESRD
CKD
Chronic
Acute
20% Sorbitol
70% Sorbitol
SPS
SPS+Sorbitol

1 with esophagus
2 with stomach
12 with small bowel
45 with colon

58 cases of gastrointestinal ischemia from 1973 to 2013 is 9 kg of kayexalate
(guessing 5 doses per episode)
58 cases
is that a lot

5 million doses of kayexalate used per year
58 cases
is that a lot

5 million doses of kayexalate used per year
150,000 kg of kayexalate
58 cases
is that a lot

avoid kayexalate in patients with sick bowels
(infection, constipation, ischemic disease, GI bleed)
avoid kayexalate in post transplant patients
avoid kayexalate enemas

CC: cough and fever
140
5.7
110
21 1.4
18
124
c. Some combination of IV 
calcium, nebulized albu- 
terol, insulin and glucose

Allon Et al. Annals of Int Med; 1989: 110, 426-429
inhaled beta-agonists are effective

• 8 studies show this works
• 20 mg works better than 10 mg
• IV administration is no better than nebulized
• additive to insulin
• may be repeated after 2 hours
Allon Et al. Annals of Int Med; 1989: 110, 426-429
inhaled beta-agonists are effective

• give regular insulin intravenously rather than subcutaneously
Blumberg Et al. Amer J Med; 1988: 85, 507-512.
as is intravenous insulin

but sodium bicarbonate is not

Blumberg Et al. Kidney International; 1992: 41, 369-374.

• 4 mmol/min for 1 hour
• 240 mmol of NaHCO3
• 0.5 mmol/min for 5 hours
• 150 mmol of NaHCO3
• Total 390 mmol NaHCO3  
(8 amps) in 1140 mL
Blumberg Et al. Kidney International; 1992: 41, 369-374.

insulin and glucose
Theoretical maximum  
134 mmol/min
14 liters x 4 mmol/liter  
= 56 mmol

insulin and glucose
Maximum hypoglycemic
effect at 100microUnits/mL
Maximum hypokalemic effect
at 500 microUnits/mL
Theoretical maximum
transport of 134 mmol/min

600
400
200
0
Maximum
kalemic effect
Maximum
glycemic effect
60 80 100 12040200
10 units of IV insulin

29 of the 221 (13%) episodes resulted in hypoglycemia.
Glucose 51–60 mg/dL in 16 episodes
Glucose ≤ 50 mg/dL in 13 episodes
All patients with hypoglycemic episodes received 25 g of
dextrose with insulin.
Hypoglycemia occurred at a median of 2 h and persisted
for a median of 2 h

Albuterol lowers the potassium independent
and additively with insulin glucose
Guhan AR, Cooper S, Oborne J, Lewis S, Bennett J, Tattersﬁeld AE. Systemic effects of formoterol
and salmeterol: a dose-response comparison in healthy subjects. Thorax. 2000;55(8):650-6.
Albuterol stimulates
glucosegenesis

potassium calcium
exchanger
Patiromer

Patiromer for Oral Suspension
(FOS) is a high capacity, non-
absorbed, oral potassium
binder.
Patiromer is a dry, odorless
powder for suspension in small
amounts of water.
Patiromer is insoluble in typical
solvents and passes through
the GI tract without being
metabolized or broken down.

CKD stage 3 or 4 Potassium 5.1–6.5 RAAS inhibitor
4 week single group
phase
8 week single blind
placebo controlled
withdrawal phase
• 52 on placebo
• 55 on patiromer
K 5.1-5.5
4.2 g bid
n=92
K 5.5-6.5
8.4 g bid
n=151
K 3.8-5.0

e. Patiromer (Veltassa)

Hyperkalemia, an update

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