Post on 16-Apr-2017
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
1405.7
11021 1.4
18124
66 year old white male
CC: cough and fever
Started on TMP-SMX 3 days ago
PMHx: CKD 3, DM2, Hypertension
1405.7
11021 1.4
18124
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
66 year old white male
CC: cough and fever
Started on TMP-SMX 3 days ago
PMHx: CKD 3, DM2, Hypertension
1405.7
11021 1.4
18124
How would you manage the potassium
a. You call that hyperka- lemia? 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
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
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
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
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
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
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
Veterans N=245,808 2,103,422 measurements of potassium
Einhorn LM. Arch Intern Med. 2009;169(12):1156-62.
Veterans N=245,808 2,103,422 measurements of potassium
0
20,000
40,000
60,000
80,000
Hyperkalemia
21,352
44,907
5.5-6.0 ≥6.0
Einhorn LM. Arch Intern Med. 2009;169(12):1156-62.
Veterans N=245,808 2,103,422 measurements of potassium
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
Einhorn LM. Arch Intern Med. 2009;169(12):1156-62.
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, 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
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
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.
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.
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.
66 year old white male
CC: cough and fever
Started on TMP-SMX 3 days ago
PMHx: CKD 3, DM2, Hypertension
1405.7
11021 1.4
18124
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
http://bit.ly/HyperK
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
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
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.”
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
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
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
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 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
150,000 kg of kayexalate
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
150,000 kg of kayexalate
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
150,000 kg of kayexalate
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
avoid kayexalate in patients with sick bowels (infection, constipation, ischemic disease, GI bleed)
avoid kayexalate in post transplant patients
avoid kayexalate enemas
66 year old white male
CC: cough and fever
Started on TMP-SMX 3 days ago
PMHx: CKD 3, DM2, Hypertension
1405.7
11021 1.4
18124
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 albu- terol, insulin and glucosed. 30 grams oral kayexalate
• 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
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
Maximum hypoglycemic effect at 100microUnits/mL
Maximum hypokalemic effect at 500 microUnits/mL
Theoretical maximum transport of 134 mmol/min
insulin and glucose
Maximum hypoglycemic effect at 100microUnits/mL
Maximum hypokalemic effect at 500 microUnits/mL
Theoretical maximum transport of 134 mmol/min
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
600
400
200
0
Maximum kalemic effect
Maximum glycemic effect
60 80 100 12040200
10 units of IV insulin
600
400
200
0
Maximum kalemic effect
Maximum glycemic effect
60 80 100 12040200
10 units of IV insulin
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
66 year old white male
CC: cough and fever
Started on TMP-SMX 3 days ago
PMHx: CKD 3, DM2, Hypertension
1405.7
11021 1.4
18124
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
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