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

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CC: cough and fever



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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


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a. You call that hyperkalemia? Do nothing.b. Stop the ACEi/ARB and TMP-SMX





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 prescriptionsTMP-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 cellS 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

G e n e r a t e s a n e g a t i v e c h a r g e i n t h e t u b u l e

dct

ccd

K +

3 Na+ 2 K+ ATPase

+

+–+–+–

Principal cellS 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

G e n e r a t e s a n e g a t i v e c h a r g e i n t h e t u b u l e

P o t a s s i u m s e c r e t i o n

dct

ccd

K +

3 Na+ 2 K+ ATPase

+

+–+–+–

Principal cell

A n y p r o 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 r e 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 R TA

( e l e c t r o g e n i c ) • P s e u d o h y p o a l d o -

s t e r o n i s m t y p e 1STOP

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.


0

20,000

40,000

60,000

80,000

Hyperkalemia

21,352

44,907

5.5-6.0 ≥6.0



0

20,000

40,000

60,000

80,000

Hyperkalemia

21,352

44,907

5.5-6.0 ≥6.0

Inci

den

ce p

er 1

,000

pat

ient

mo

nths

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

Od

ds

Rat

io o

f dea

th in

1 d

ay

0

10

20

30

40

No CKD CKD 3 CKD 4 CKD 5

8.011.6

19.5

31.6

2.35.75.4

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.

5,945 patients died within 1 day of a potassium measurement, % deaths for K and CKD status

% o

f po

tass

ium

with

a d

eath

in 2

4 ho

urs

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


5,945 patients died within 1 day of a potassium measurement, % deaths for K and CKD status

% o

f po

tass

ium

with

a d

eath

in 2

4 ho

urs

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±12.1Age

female male

AsianBlack/African American

WhiteWeight

potassium

<5.5

5.5-6.0

≥6.0

5.6

50%

35%

14%

eGFR

open

labe

l tre

at

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±9.1Age

femalemale White

Weight

potassium 4.455.9

eGFR

4.6

85.1±18.6

35.4±16.2

5.17

K ≥ 5.5

open

labe

l tre

at

blin

ded

plac

ebo

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



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1938

Food, Drug, and Cosmetic Act

1962

Kefauver, Harris Amendment

10 oliguric patientsTreated with Sorbitol,

SPS, or both.

Sorbitol aloneSPS in blue

Sorbitol aloneSPS in bluePo

tass

ium

(mm

ol/

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

Num

ber

of p

atie

nts

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

that was enough for approval

Pota

ssiu

m (m

mo

l/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

Pota

ssiu

m (m

mo

l/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

106

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

106

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.”

1938

Food, Drug, and Cosmetic Act

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

3124

3

23 case reports

30 articles

7 case series

58 cases

0

10

20

30

40

Before 1990 1990-2000 After 2000

3124

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

3124

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

3124

3

women

men

mean age 58 years

No CKD

ESRDCKD

23 case reports

30 articles

7 case series

58 cases

0

10

20

30

40

Before 1990 1990-2000 After 2000

3124

3

women

men

mean age 58 years

No CKD

ESRDCKD

ChronicAcute

23 case reports

30 articles

7 case series

58 cases

0

10

20

30

40

Before 1990 1990-2000 After 2000

3124

3

women

men

mean age 58 years

No CKD

ESRDCKD

ChronicAcute

SPS

SPS+Sorbitol

23 case reports

30 articles

7 case series

58 cases

0

10

20

30

40

Before 1990 1990-2000 After 2000

3124

3

women

men

mean age 58 years

No CKD

ESRDCKD

ChronicAcute

20% Sorbitol

70% Sorbitol

SPS

SPS+Sorbitol

45 with colon

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



5 million doses of kayexalate used per year

150,000 kg of kayexalate



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

avoid kayexalate in post transplant patients

avoid kayexalate enemas


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c. Some combination of IV calcium, nebulized albuterol, insulin and glucosed. 30 grams oral kayexalate

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



• give regular insulin intravenously rather than subcutaneously

Blumberg Et al. Amer J Med; 1988: 85, 507-512.

as is intravenous insulin

Blumberg Et al. Amer J Med; 1988: 85, 507-512.

but sodium bicarbonate is not

Blumberg Et al. Amer J Med; 1988: 85, 507-512. 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. Amer J Med; 1988: 85, 507-512. Blumberg Et al. Kidney International; 1992: 41, 369-374.

insulin and glucose

Theoretical maximum

134 mmol/min14 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


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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

Health & Medicine