Hyperkalemia in patients

with chronic kidney disease.

Liang Meng Tzu

2016.01.27

Total B

ody W

ater ~

45

L60% body weight

Body Fluid Distribution

The Renal System Explained: An Illustrated Core Text by Sunita R

1mEq/kg/day

10% excretion

90% excretion

(2/3)

(1/3)

Hyperkalemia

� Hyperkalemia:

Hyperkalemia is defined as a serum potassium concentration

higher than the upper limit of the normal range(3.5-5.0 mEq/L).

Most common is >5.0 mEq/L .

Mild：5.0-6.0 mEq/L

Moderate：6.1-7.0 mEq/L

Severe：≥7.0 mEq/L

� Most common risk factor for hyperkalemia is CKD and CVD Patients.

� Epidemiology of hyperkalaemia ：

General population：2–3%

Patients with CKD：40–50%

Renal potassium handling

(Thick ascending limb)

(Cortical collecting duct)

Principal

cells

Intercalated

cells

65%

作用弱

k+ k+

30%

運輸蛋白運輸蛋白運輸蛋白運輸蛋白NKCC2

大量k+釋出

少量k+回收

Molecular Diversity and Regulation of Renal Potassium Channels.Physiol Rev 85: 319

作用弱

(Outer medullary collecting

duct)

K+

Cl-

Regulation of extracellular fluid

potassium concentration

Major causes of hyperkalemia

Increased potassium release from cells

Pseudohyperkalemia

Trauma during venipuncture,Leukocytosis,Thrombocytosis, Exercise

Metabolic acidosis

Insulin deficiency,Hyperglycemia

Increased tissue catabolism

Reduced urinary potassium excretion

Reduced aldosterone secretion, Reduced response to aldosterone

Acute and chronic kidney disease

Major causes of hypoaldosteronism

Palmer BF. N Engl J Med 2004;351:585

Reduced aldosterone production

Hyporeninemic hypoaldosteronism

Renal disease, most often diabetic nephropathy

Nonsteroidal anti-inflammatory drugs

Calcineurin inhibitors

Angiotensin inhibitors(ACEI, ARB, direct renin

inhibitors)

Primary adrenal insufficiency

Aldosterone resistance

Inhibition of the epithelial sodium channel

Potassium-sparing diuretics, such as

spironolactone, eplerenone, amiloride,

and triamterene

Antibiotics, trimethoprim, and pentamidine

Importance of Treatment of CKD patients with

RAAS Inhibitors

� In patients with diabetes and protein

uria, therapy with an ACEI or an ARB

slows progression of renal disease.

� RAAS inhibitor monotherapy is associated

with hyperkalemia relatively infrequently

in patients with normal kidney function

( < 2%), but its incidence increases to 5%

with dual therapy and to 5%-10% when

dual therapy is administered to patients

with chronic kidney disease.

N Engl J Med 2004;351:585-92.

� Discontinue drugs that interfere in renal potassium secretion.

� Prescribe low-potassium diet.

� Prescribe thiazide or loop diuretics. (loop diuretics necessary when estimated glomerular

filtration rate is

� If potassium increases to ≤5.5 mmol/liter, decrease dose of drug; if patient is taking some

combination of an ACE inhibitor, an angiotensin-receptor blocker, and an aldosterone-receptor

blocker, discontinue one and recheck potassium.

� The dose of spironolactone should not exceed 25 mg daily when used with an ACE inhibitor or

angiotensin-receptor blocker; this combination of drugs should be avoided when the glomerular

filtration rate is 5.5 mmol/liter despite steps described above, discontinue drugs.

Clinical features

� Muscle weakness or paralysis

� Cardiac manifestations

ECG changes:>6.5mEq/L

Conduction abnormalities and arrhythmias

� Reduced urinary acid excretion Am Fam Physician. 2006 Jan 15;73(2):283

6~7 mEq/L

7~8 mEq/L

8~9 mEq/L

Management Options for Hyperkalemia

Antagonism of membrane actions of potassium

Calcium

Drive extracellular potassium into the cells

Insulin and glucose

Sodium bicarbonate, primarily if metabolic acidosis

β2-adrenergic agonists

Removal of potassium from the body

Loop or thiazide diuretics

Cation exchange resin

Dialysis, preferably hemodialysis if severe

Antagonism of membrane actions of potassium

Calcium chloride (10%), or calcium gluconate (10%)

Mechanism Membrane potential stabilization

Dose 6.8 mmol of calcium; corresponding to 10 mL calcium chloride or 30 mL calcium gluconate

Route IV (acute); calcium chloride is caustic and may damage peripheral veins (A central vein is preferred for administration of calcium chloride. If a peripheral vein

is used, calcium gluconate should be used. )

Onset 1-3 minutes

Duration 30-60 minutes

- Does not affect serum potassium level

- Should not be given in bicarbonate-containing solutions → Calcium carbonate- Dose can be repeated after five minutes if the ECG changes persist or recur

- Caution advised in patients on digoxin → calcium gluconate should be added to 100 mL of 5 percent dextrose in water and infused over 20 to 30 minutes.

Solution Elemental Calcium Unit Volume Osmolarity

10% Calcium Chloride 27 mg (1.36 mEq)/mL 10-mL Ampules 2000 mOsm/L

10% Calcium Gluconate 9 mg (0.46 mEq)/mL 10-mL ampules 680 mOsm/L

Drive extracellular potassium into the cells

Insulin

Mechanism Redistribution(Enhancing the activity of the Na-K-ATPase pump in skeletal muscle)

Dose 10~20 units of regular insulin

Route IV (acute)

Onset 30 minutes

Duration 4-6 hours

Lowering the serum potassium concentration by 0.5 to 1.2 meq/L.

-Administer with 50 g (500 ml of 10% dextrose) of glucose to prevent hypoglycemia.

-Administer with 25 g (50 ml of 50% dextrose) of glucose to prevent hypoglycemia

→ Hypoglycemia occurs in up to 75% → Infusion of 10% dextrose at 50 ~75 mL/hour-Insulin should be given alone if the serum glucose is ≥ 250 mg/dL.

-The serum glucose should be measured one hour after the administration of insulin.

-Administration of glucose without insulin is not recommended.

Drive extracellular potassium into the cells

Beta-2 agonists

Mechanism Redistribution(Enhancing the activity of the Na-K-ATPase pump in skeletal muscle)

Dose 10-20 mg in 4 mL of saline (Nebulized) or 0.5 mg in 100 mL of D5W (IV infusion)

Route IV or nebulized (both acute)

Onset 30 minutes(IV infusion)90 minutes(Nebulized)

Duration 2-4 hours

Lowering the serum potassium concentration by 0.5 to 1.5 meq/L.

(Beta-2 agonists + Insulin + Glucose：1.2 to 1.5 meq/L)

- Selective beta-2 agonist：Albuterol- Subcutaneous terbutaline is a potential alternative

- Caution in patients with known CAD (tachycardia and induction of angina)

Drive extracellular potassium into the cells

Na bicarbonate

Mechanism Redistribution(Hydrogen ion release from the cell as part of the buffering reaction.)

Dose Isotonic solution：150 mEq in 1L of 5% dextrose in water at 250 mL/hourHypertonic solution：1 standard ampule of 50 mEq of sodium bicarbonate in 50 ml

Route IV (acute) or PO (chronic)

- Provides minimal effect on shifting potassium intracellularly , even in acidemic

patients

- Do not given in same IV as calcium

- Can lead to hypernatremia

- Efficacy for acute treatment in dialysis patients recently questioned

Ironically, this dogma was based on studies using a prolonged (4–6 hrs) infusion of bicarbonate . It

has now been clearly demonstrated that short term bicarbonate infusion does not reduce PK in

patients with dialysis-dependent kidney failure, implying that it does not cause K shift into cells.

Infusion of a hypertonic or an isotonic bicarbonate solution for 60 mins has been shown to have no

effect on PK in dialysis patients, despite a substantial increase in serum bicarbonate concentration.

Only after a 4-hr infusion was a small (0.6 mmol/L) but significant decrease in PK is detectable.Management of severe hyperkalemia.Crit Care Med 2008 Vol. 36, No. 12

Removal of potassium from the body

Diuretics

Mechanism

Excretion(Increase potassium loss in the urine)

Dose 20 to 40 mg furosemide or equivalent dose of other loop diuretic.(Combined with saline hydration)

Higher dose may be needed with advanced chronic kidney disease.

Route IV (acute) or PO (chronic)

Onset Varies with start of diuresis

Duration Until diuresis present or longer

- Loop diuretics for acute intervention

- Loop or thiazide diuretics for chronic management

Removal of potassium from the body

Cation exchange resins

Mechanism Excretion(Takes up potassium and releases sodium. )

Dose PO：15-30 g,Q4-Q6H；Enema：50g SPS is mixed with 150mL of tap water

Route PO with or without sorbitol or Retention enema

Onset 1-2 hours

Duration 4-6 hours or longer

- Sodium polystyrene sulfonate(SPS,Kayexalate) only approved agent in most countries

- Calcium polystyrene sulfonate approved in some countries

- Potassium exchange capacity：2 to 3.1 mEq/g in vitro and 1 mEq/g in vivo.- Kayexalate is more selective for Ca2+、Mg2+ than K+ .

Sodium polystyrene sulfonate(SPS,Kayexalate)

� 1958 approved by FDA.

� 2009 FDA warning：

� SPS with or without sorbitol should not be given to the following patients because they may be at high risk for intestinal necrosis:

1. Postoperative patients or patient who have received a kidney transplant

2. Patients with an ileus or bowel obstruction

� 2015 FDA requires drug interaction studies：

Colonic NecrosisCases of colonic necrosis and other serious gastrointestinal adverse events (bleeding, ischemic

colitis, perforation) have been reported in association with Kayexalate use. The majority of

these cases reported the concomitant use of sorbitol. Risk factors for gastrointestinal adverse

events were present in many of the cases including prematurity, history of intestinal disease

or surgery hypovolemia, and renal insufficiency and failure. Concomitant administration of

sorbitol is not recommended.

Similar to Veltassa, Kayexalate may also bind to other medications administered by mouth. To

reduce this potential risk, prescribers and patients should consider separating Kayexalate

dosing from other medications taken by mouth by at least 6 hours.

Patiromer(Veltassa® ) - 2015.10.21 approved by FDA.

• Calcium exchanged for potassium.

• Binds potassium predominantly in colon.

• Veltassa increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract. Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, resulting in a reduction of serum potassium levels.

• Veltassa is a powder for suspension in water for oral administration.

Patiromer(Veltassa ) - 2015.10.21 approved by FDA.

Indications Hyperkalemia.Limitation of use： Veltassa should not be used as an emergency treatment for life-threatening hyperkalemia .(onset：7 hours)

Dosage forms 8.4 grams, 16.8 grams or 25.2 grams

Dose Starting dose ：8.4 grams orally once daily with food.(Max： 25.2 grams once daily)Adjust dose by 8.4 grams daily as needed at one week intervals.

Warnings Binding to Other Orally Administered MedicationsAdminister other oral medications at least 6 hours before or 6 hours after Veltassa.

Worsening of Gastrointestinal Motility

Avoid use in patients with severe constipation, bowel obstruction or impaction,

including abnormal post-operative bowel motility disorders.

Hypomagnesemia

Veltassa binds to magnesium in the colon, which can lead to

hypomagnesemia.(5.3%)

ADR

Patiromer(Veltassa )

� STE 1: MIX

� STE 2: ADD

� STE 3: DRINK

HOW SHOULD I STORE VELTASSA?

�VELTASSA should be stored in the refrigerator at 36°F to 46°F (2°C to 8°C). As long as it’s kept in the refrigerator, VELTASSA can be used until the expiration date printed on the packet.

�If VELTASSA is stored at room temperature (73°F to 81°F [23°C to 27°C]), it must be used within 3 months of being taken out of the refrigerator.

�Regardless of whether you store VELTASSA in the refrigerator or at room temperature, do not use VELTASSA after the expiration date printed on the packet.

�Avoid exposing VELTASSA to excessive heat above 104°F (40°C).

With CKD

and on RAAS

inhibitor

Part ASingle-Blind

Uncontrolled

n=237

Responders with

Part A Baseline

Potassium 5.5 ~

Sodium Polystyrene Sulfonate Patiromer (Valtessa) Sodium Zirconium Cyclosilicilate (ZS-9)

FDA approval 1958 2015 Pending

Mechanism of action

Nonspecific sodium-cation

exchange resin

Calcium-potassium cation

exchange resin

Selective potassium cation

trapping agent

(>125 times more than SPS)

Counter-ion bound Sodium Calcium Sodium and hydrogen

Formulation Oral suspensionPowder for reconstitution

Rectal enema

Oral suspension Oral suspension

Dissolvable tablet

Onset of action 1 to 2 hours 7 hours 1 hour

Dosing 15–60 g/day orally (1–4 times daily)30–50 g/day rectally (up to 4 times

daily)

8.4–25.2 g once daily 5–10 g once daily pending

FDA approval

Common adverse events

GI disturbances

Electrolyte disorders

(e.g., hypokalemia,

hypomagnesemia, hypocalcemia)

Systemic alkalosis

GI disturbances

Hypokalemia

Possible calcium load

Hypomagnesemia

GI disturbances

Hypokalemia

Serious ADR Colonic necrosis None NonePotassium-Binding Agents for Treatment of Patients With Hyperkalemia.PT. 2

Removal of potassium from the body

Dialysis

Mechanism Removal

Route Hemodialysis(acute or chronic) or peritoneal dialysis (chronic)

Onset Within minutes after starting treatment

Duration Until end of dialysis or longer

- It is preferred treatment in patients with renal failure,or marked tissue breakdown.

- Additional effects of dialysis on serum sodium, bicarbonate, calcium, or magnesium

may affect results

- Hemodialysis can remove 25 to 50mEq of potassium per hour

Low-potassium diet

References

� 1.Treatment and prevention of hyperkalemia in adults.Uptodate.

� 2.Clinical Update on Hyperkalemia.National Kidney Foundation.

� 3.Management of Hyperkalemia：An Update for the Internist.The

American Journal of Medicine.

� 4. Relypsa 2014 Annual Report.