TREATMENT OF HYPERKALEMIA IN CKD REFERENCES The steps to address hyperkalemia include stabilization, redistribution, and excretion/removal of potassium. + 1. Tran HA. Extreme hyperkalemia. 11. Inker LA, Astor BC, Fox CH, et al. KDOQI U.S. Best Practices in Managing South Med J. 2005;98:729-732. commentary on the 2012 KDIGO clinical Table 3. Summary of interventions used for acute or chronic treatment of hyperkalemia6 practice guideline for the evaluation and K 2. Gumz ML, Rabinowitz L, Wingo CS. An HYPERKALEMIA integrated view of potassium homeostasis. management of CKD. Am J Kidney Dis. May Treatment Route of Onset/ Mechanism Comments N Engl J Med. 2015;373:60-72. 2014;63(5):713-735. in Chronic Kidney Disease administration duration 3. Alvo M, Warnock DG. Hyperkalemia. 12. Mercier K, Smith H, Biederman J. Renin- West J Med. 1984;141:666-671. angiotensin-aldosterone system 6.8 mmol of calcium, corresponding Intravenous (acute) 1-3 min Membrane „„ Does not affect serum potassium level inhibition: overview of the therapeutic 4. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of to 10 ml CaCl (10%)* or 30 ml 30-60 min potential stabilization „„ Effect measured by normalization of electrocardiographic changes use of angiotensin-converting enzyme calcium gluconate (10%) solutions „„ Dose can be repeated if no effects noted hyperkalemia and its significance in chronic kidney inhibitors, angiotensin receptor blockers, „„ Caution advised in patients receiving digoxin disease. Arch Intern Med. 2009;169:1156-1162. mineralocorticoid receptor antagonists, 50-250 ml hypertonic saline (3-5%)** Intravenous (acute) 5-10 min Membrane „„ Efficacy only in hyponatremic patients 5. Jain N, Kotla S, Little BB, et al. Predictors of and direct renin inhibitors. Prim Care. ~2 h potential stabilization hyperkalemia and death in patients with 2014;41:765-778. cardiac and renal disease. Am J Cardiol. 50-100 mmol sodium bicarbonate Intravenous (acute) 5-10 min Redistribution „„ Sodium may worsen pre-existing hypertension and heart failure 13. Vassalotti JA, Centor R, Turner BJ, et al; U.S. 2012;109:1510-1513. or oral (chronic) ~2 h „„ Efficacy questioned for acute treatment of patients on dialysis Kidney Disease Outcomes Quality Initiative 6. Kovesdy CP. Management of hyperkalaemia (KDOQI). A practical approach to detection 10 units of regular insulin Intravenous (acute) 30 min Redistribution „„ Administer with 50 g of glucose intravenously to prevent hypoglycemia in chronic kidney disease. Nat Rev Nephrol. and management of chronic kidney disease 4-6 h 2014;10:653-662. for the primary care clinician [Epub ahead of ß2-receptor agonists: Intravenous or 30 min Redistribution „„ Effect independent of insulin and aldosterone 7. Sarafidis PA, Blacklock R, Wood E, et al. print September 18 2015]. Am J Med. 2015. 10-20 mg aerosol (nebulized) or nebulized (both 2-4 h „„ Caution in patients with known coronary artery disease 0.5mg in 100ml of 5% dextrose in acute) Prevalence and factors associated with 14. Lehnhardt A, Kemper MJ. Pathogenesis, water (intravenous) hyperkalemia in predialysis patients followed in diagnosis, and management of a low-clearance clinic. Clin J Am Soc Nephrol. hyperkalemia. Pediatr Nephrol. March 40 mg furosemide or equivalent Intravenous (acute) Varies Excretion „„ Loop diuretics for acute intervention 2012;7:1234-1241. 2011;26:377-384. dose of other loop diuretic. Higher or oral (chronic) Until diuresis „„ Loop or thiazide diuretics for chronic management; loop diuretic for GFR <40 ml/min/1.73 m2 15 8. Turgut F, Balogun RA, Abdel-Rahman 15. Sarafidis PA, Georgianos PI, Bakris GL. doses may be needed in patients present or „„ May not be effective in patients with reduced GFR EM. Renin-angiotensin-aldosterone system with advanced CKD longer Advances in treatment of hyperkalemia blockade effects on the kidney in the elderly: in chronic kidney disease. Expert Opin Fludrocortisone acetate ≥0.1 mg Oral (chronic) NA Excretion „„ In patients with aldosterone deficiency, large doses might be needed to effectively lower benefits and limitations. Clin J Am Soc Pharmacother. 2015;16:2205-2215. (up to 0.4-1.0 mg daily) potassium levels Nephrol. 2010;5:1330-1339. „„ Sodium retention, edema, and hypertension might occur, and acceleration of kidney and 16. U.S. Food and Drug Administration (FDA). cardiovascular disease 9. Xie X, Liu Y, Perkovic V, et al. Renin-angiotensin Kayexalate. http://www.accessdata.fda.gov/ system inhibitors and kidney and drugsatfda_docs/label/2011/011287s023lbl. Cation exchange resins Oral or rectal (either 1-2 h Excretion „„ Cases of intestinal necrosis, which may be fatal, and other serious GI adverse events have cardiovascular outcomes in patients with pdf. Updated December 2010. Accessed Sodium polystyrene sulfonate acute or chronic), �4-6 h been reported16 CKD: a Bayesian Network meta-analysis of December 22 2015. 25-50 g with or without „„ May cause hypokalemia and electrolyte disturbances16 randomized clinical trials [Epub ahead of print sorbitol „„ Cannot be used in medical emergencies16 17. U.S. Food and Drug Administration (FDA). FDA ›› Hyperkalemia in Chronic Kidney Disease (CKD) 16 November 17 2015]. Am J Kidney Dis. 2015. „„ Caution in patients with heart failure due to sodium load approves new drug to treat hyperkalemia. ›› Treatment with RAAS Inhibitors (RAASi) in CKD 10. Kidney Disease: Improving Global Outcomes Cation exchange polymer Oral (either acute 7 h Excretion „„ Binds with many other oral medications (in vitro binding studies), separate the dosing of other http://www.fda.gov/NewsEvents/Newsroom/ (KDIGO) CKD Work Group. KDIGO 2012 ›› Diagnosis and Evaluation of Hyperkalemia Patiromer 8.4, 16.8, or 25.2 g or chronic) ~48 h oral medications by at least 6 hours 17 *** PressAnnouncements/ucm468546.htm. „„ Should not be used as an emergency treatment for life-threatening hyperkalemia because clinical practice guideline for the evaluation Published October 22 2015. Accessed ›› Treatment of Hyperkalemia in CKD of its delayed onset of action17 and management of chronic kidney disease. November 24 2015. „„ May result in hypokalemia or hypomagnesemia17 Kidney Int Suppls. 2013;3:1-150. Dialysis Hemodialysis Within Removal „„ Effects of dialysis on serum sodium, bicarbonate, calcium and/or magnesium levels can affect results (acute or chronic); minutes „„ For chronic hemodialysis, missed treatments and 2-day interdialytic interval may have a Peritoneal dialysis Until end of negative impact on outcomes. (chronic) dialysis or This publication has been sponsored and longer**** developed in collaboration with Relypsa, Inc.

30 East 33rd Street *CaCl is caustic and could damage peripheral veins. **Limited data available from clinical studies. ***Clinical studies being done to assess the clinical significance of the in vitro interaction. ****Effects can New York, NY 10016 last for an unspecified length of time, depending on ongoing potassium intake or cellular redistribution. Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; GI, gastrointestinal; NA, not 800.622.9010 applicable. | Adapted with permission from Kovesdy CP. Management of hyperkalaemia in chronic kidney disease. Nat Rev Nephrol, 2014;10:659-662. Copyright 2014 by Macmillan Publishers Limited. www.kidney.org © 2016 National Kidney Foundation, Inc. 02-10-7259_LBG HYPERKALEMIA TREATMENT WITH RAASi DIAGNOSIS AND EVALUATION IN CKD IN CKD OF HYPERKALEMIA

The definition of hyperkalemia varies and limits such as >5.5, Studies show that use of ACEIs or ARBs in people with CKD reduces the Hyperkalemia is often asymptomatic, but patients may complain 1 >6.0, or >7.0 mEq/L are used to indicate severity. Repetitive Table 2. Chronic Risk Factors for risk for kidney failure and cardiovascular events, but their use contributes of nonspecific symptoms such as palpitations, nausea, muscle consecutive measures of serum potassium are needed Hyperkalemia in CKD 5, 6, 7, 8 to hyperkalemia.9 The clinical practice guidelines for the use of RAASi in pain, weakness, or paresthesia. Moderate and especially severe to determine if hyperkalemia is sustained or a transient event. CKD are as follows:10, 11 hyperkalemia can lead to cardiotoxicity, which can be fatal. The Many factors affect potassium homeostasis.2 cause of hyperkalemia has to be determined to prevent future episodes. 14 Risk Factor Due To „„KDIGO Guidelines suggest that an ARB or ACEI be used in diabetic adults with CKD and urine albumin excretion 30-300 mg/24 hours (or equivalent). (2D) Potassium intake Increased dietary potassium intake from Table 1. Acute Versus Chronic Hyperkalemia 3, 4 salt substitute, potassium-rich heart-healthy „„KDIGO Guidelines recommend that an ARB or ACEI be used in Emergency diagnostic Elective/etiologic diets, and herbal supplements both diabetic and nondiabetic adults with CKD and urine albumin workup:14 workup:14 Acute Hyperkalemia Chronic Hyperkalemia Metabolic acidosis Potassium shift from the intracellular to the excretion >300 mg/24 hours (or equivalent). (1B) extracellular space 1. A ssessment of cardiac function, 1. Comprehensive laboratory workup „„There is insufficient evidence to recommend combining an kidneys, and urinary tract Caused by abnormal net release of Caused by impairment of RAASi Treatment with ACEIs and ARBs block the ACEI with ARBs to prevent progression of CKD. (Not Graded) 2. Review of medication used potassium from cells, often due to potassium excretory process renin-angiotensin system and cause lower 2. Assessment of hydration status trauma, metabolic acidosis (depends and/or increased potassium load serum aldosterone ƒƒ Subsequent research shows that dual RAAS inhibition with ACEI on etiology), hemolytic states plus ARB not only fails to improve cardiovascular or renal outcomes, 3. Electrocardiogram 12 Diabetes Insulin deficiency and hypertonicity caused but predisposes patients to serious adverse events. by hyperglycemia contribute to an inability Requires immediate attention, ie, Requires ongoing management to disperse high acute potassium load into cardiac monitoring, acute medical to correct the underlying the intracellular space interventions, possibly dialysis disturbances in potassium balance, Considerations for using an ACEI or ARB in patients with CKD: ie, nonpharmacological and pharmacological interventions Heart failure Reduction in renal perfusion, use of RAASi or MRA „„Hyperkalemia and worsening kidney function can develop. Disclaimer: Information contained in this Management goals: induce Management goals: induce Coronary artery and Use of RAASi, oxidative stress, „„It is important to monitor serum potassium and estimated potassium redistribution and potassium redistribution peripheral vascular disease atherosclerosis glomerular filtration rate (eGFR) within several weeks of starting National Kidney Foundation excretion, restore normal and excretion to prevent the educational resource is based or escalating a RAASi.13 electrophysiology of the cell development or recurrence of upon current data available at the Advanced age Decreases in plasma renin activity and membrane, prevent cardiac hyperkalemia; monitor potassium time of publication. Information is arrhythmia intake through diet plasma aldosterone levels with age, as well „„Discontinuing these drugs is helpful in controlling or treating as frequent use of NSAIDS in this population. intended to help clinicians become hyperkalemia, but the disadvantage is that it increases the risk aware of new scientific findings and for kidney disease progression and cardiovascular events.6 developments. This clinical bulletin is not intended to set out a preferred Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor standard of care and should not be blocker; MRA, mineralocorticoid receptor antagonist; NSAIDS, nonsteroidal anti-inflammatory drugs; RAASi, renin-angiotensin-aldosterone system inhibitors. construed as one. Neither should the information be interpreted as prescribing an exclusive course of management. HYPERKALEMIA TREATMENT WITH RAASi DIAGNOSIS AND EVALUATION IN CKD IN CKD OF HYPERKALEMIA

The definition of hyperkalemia varies and limits such as >5.5, Studies show that use of ACEIs or ARBs in people with CKD reduces the Hyperkalemia is often asymptomatic, but patients may complain 1 >6.0, or >7.0 mEq/L are used to indicate severity. Repetitive Table 2. Chronic Risk Factors for risk for kidney failure and cardiovascular events, but their use contributes of nonspecific symptoms such as palpitations, nausea, muscle consecutive measures of serum potassium are needed Hyperkalemia in CKD 5, 6, 7, 8 to hyperkalemia.9 The clinical practice guidelines for the use of RAASi in pain, weakness, or paresthesia. Moderate and especially severe to determine if hyperkalemia is sustained or a transient event. CKD are as follows:10, 11 hyperkalemia can lead to cardiotoxicity, which can be fatal. The Many factors affect potassium homeostasis.2 cause of hyperkalemia has to be determined to prevent future episodes. 14 Risk Factor Due To „„KDIGO Guidelines suggest that an ARB or ACEI be used in diabetic adults with CKD and urine albumin excretion 30-300 mg/24 hours (or equivalent). (2D) Potassium intake Increased dietary potassium intake from Table 1. Acute Versus Chronic Hyperkalemia 3, 4 salt substitute, potassium-rich heart-healthy „„KDIGO Guidelines recommend that an ARB or ACEI be used in Emergency diagnostic Elective/etiologic diets, and herbal supplements both diabetic and nondiabetic adults with CKD and urine albumin workup:14 workup:14 Acute Hyperkalemia Chronic Hyperkalemia Metabolic acidosis Potassium shift from the intracellular to the excretion >300 mg/24 hours (or equivalent). (1B) extracellular space 1. A ssessment of cardiac function, 1. Comprehensive laboratory workup „„There is insufficient evidence to recommend combining an kidneys, and urinary tract Caused by abnormal net release of Caused by impairment of RAASi Treatment with ACEIs and ARBs block the ACEI with ARBs to prevent progression of CKD. (Not Graded) 2. Review of medication used potassium from cells, often due to potassium excretory process renin-angiotensin system and cause lower 2. Assessment of hydration status trauma, metabolic acidosis (depends and/or increased potassium load serum aldosterone ƒƒ Subsequent research shows that dual RAAS inhibition with ACEI on etiology), hemolytic states plus ARB not only fails to improve cardiovascular or renal outcomes, 3. Electrocardiogram 12 Diabetes Insulin deficiency and hypertonicity caused but predisposes patients to serious adverse events. by hyperglycemia contribute to an inability Requires immediate attention, ie, Requires ongoing management to disperse high acute potassium load into cardiac monitoring, acute medical to correct the underlying the intracellular space interventions, possibly dialysis disturbances in potassium balance, Considerations for using an ACEI or ARB in patients with CKD: ie, nonpharmacological and pharmacological interventions Heart failure Reduction in renal perfusion, use of RAASi or MRA „„Hyperkalemia and worsening kidney function can develop. Disclaimer: Information contained in this Management goals: induce Management goals: induce Coronary artery and Use of RAASi, oxidative stress, „„It is important to monitor serum potassium and estimated potassium redistribution and potassium redistribution peripheral vascular disease atherosclerosis glomerular filtration rate (eGFR) within several weeks of starting National Kidney Foundation excretion, restore normal and excretion to prevent the educational resource is based or escalating a RAASi.13 electrophysiology of the cell development or recurrence of upon current data available at the Advanced age Decreases in plasma renin activity and membrane, prevent cardiac hyperkalemia; monitor potassium time of publication. Information is arrhythmia intake through diet plasma aldosterone levels with age, as well „„Discontinuing these drugs is helpful in controlling or treating as frequent use of NSAIDS in this population. intended to help clinicians become hyperkalemia, but the disadvantage is that it increases the risk aware of new scientific findings and for kidney disease progression and cardiovascular events.6 developments. This clinical bulletin is not intended to set out a preferred Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor standard of care and should not be blocker; MRA, mineralocorticoid receptor antagonist; NSAIDS, nonsteroidal anti-inflammatory drugs; RAASi, renin-angiotensin-aldosterone system inhibitors. construed as one. Neither should the information be interpreted as prescribing an exclusive course of management. HYPERKALEMIA TREATMENT WITH RAASi DIAGNOSIS AND EVALUATION IN CKD IN CKD OF HYPERKALEMIA

The definition of hyperkalemia varies and limits such as >5.5, Studies show that use of ACEIs or ARBs in people with CKD reduces the Hyperkalemia is often asymptomatic, but patients may complain 1 >6.0, or >7.0 mEq/L are used to indicate severity. Repetitive Table 2. Chronic Risk Factors for risk for kidney failure and cardiovascular events, but their use contributes of nonspecific symptoms such as palpitations, nausea, muscle consecutive measures of serum potassium are needed Hyperkalemia in CKD 5, 6, 7, 8 to hyperkalemia.9 The clinical practice guidelines for the use of RAASi in pain, weakness, or paresthesia. Moderate and especially severe to determine if hyperkalemia is sustained or a transient event. CKD are as follows:10, 11 hyperkalemia can lead to cardiotoxicity, which can be fatal. The Many factors affect potassium homeostasis.2 cause of hyperkalemia has to be determined to prevent future episodes. 14 Risk Factor Due To „„KDIGO Guidelines suggest that an ARB or ACEI be used in diabetic adults with CKD and urine albumin excretion 30-300 mg/24 hours (or equivalent). (2D) Potassium intake Increased dietary potassium intake from Table 1. Acute Versus Chronic Hyperkalemia 3, 4 salt substitute, potassium-rich heart-healthy „„KDIGO Guidelines recommend that an ARB or ACEI be used in Emergency diagnostic Elective/etiologic diets, and herbal supplements both diabetic and nondiabetic adults with CKD and urine albumin workup:14 workup:14 Acute Hyperkalemia Chronic Hyperkalemia Metabolic acidosis Potassium shift from the intracellular to the excretion >300 mg/24 hours (or equivalent). (1B) extracellular space 1. A ssessment of cardiac function, 1. Comprehensive laboratory workup „„There is insufficient evidence to recommend combining an kidneys, and urinary tract Caused by abnormal net release of Caused by impairment of RAASi Treatment with ACEIs and ARBs block the ACEI with ARBs to prevent progression of CKD. (Not Graded) 2. Review of medication used potassium from cells, often due to potassium excretory process renin-angiotensin system and cause lower 2. Assessment of hydration status trauma, metabolic acidosis (depends and/or increased potassium load serum aldosterone ƒƒ Subsequent research shows that dual RAAS inhibition with ACEI on etiology), hemolytic states plus ARB not only fails to improve cardiovascular or renal outcomes, 3. Electrocardiogram 12 Diabetes Insulin deficiency and hypertonicity caused but predisposes patients to serious adverse events. by hyperglycemia contribute to an inability Requires immediate attention, ie, Requires ongoing management to disperse high acute potassium load into cardiac monitoring, acute medical to correct the underlying the intracellular space interventions, possibly dialysis disturbances in potassium balance, Considerations for using an ACEI or ARB in patients with CKD: ie, nonpharmacological and pharmacological interventions Heart failure Reduction in renal perfusion, use of RAASi or MRA „„Hyperkalemia and worsening kidney function can develop. Disclaimer: Information contained in this Management goals: induce Management goals: induce Coronary artery and Use of RAASi, oxidative stress, „„It is important to monitor serum potassium and estimated potassium redistribution and potassium redistribution peripheral vascular disease atherosclerosis glomerular filtration rate (eGFR) within several weeks of starting National Kidney Foundation excretion, restore normal and excretion to prevent the educational resource is based or escalating a RAASi.13 electrophysiology of the cell development or recurrence of upon current data available at the Advanced age Decreases in plasma renin activity and membrane, prevent cardiac hyperkalemia; monitor potassium time of publication. Information is arrhythmia intake through diet plasma aldosterone levels with age, as well „„Discontinuing these drugs is helpful in controlling or treating as frequent use of NSAIDS in this population. intended to help clinicians become hyperkalemia, but the disadvantage is that it increases the risk aware of new scientific findings and for kidney disease progression and cardiovascular events.6 developments. This clinical bulletin is not intended to set out a preferred Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor standard of care and should not be blocker; MRA, mineralocorticoid receptor antagonist; NSAIDS, nonsteroidal anti-inflammatory drugs; RAASi, renin-angiotensin-aldosterone system inhibitors. construed as one. Neither should the information be interpreted as prescribing an exclusive course of management. HYPERKALEMIA TREATMENT WITH RAASi DIAGNOSIS AND EVALUATION IN CKD IN CKD OF HYPERKALEMIA

The definition of hyperkalemia varies and limits such as >5.5, Studies show that use of ACEIs or ARBs in people with CKD reduces the Hyperkalemia is often asymptomatic, but patients may complain 1 >6.0, or >7.0 mEq/L are used to indicate severity. Repetitive Table 2. Chronic Risk Factors for risk for kidney failure and cardiovascular events, but their use contributes of nonspecific symptoms such as palpitations, nausea, muscle consecutive measures of serum potassium are needed Hyperkalemia in CKD 5, 6, 7, 8 to hyperkalemia.9 The clinical practice guidelines for the use of RAASi in pain, weakness, or paresthesia. Moderate and especially severe to determine if hyperkalemia is sustained or a transient event. CKD are as follows:10, 11 hyperkalemia can lead to cardiotoxicity, which can be fatal. The Many factors affect potassium homeostasis.2 cause of hyperkalemia has to be determined to prevent future episodes. 14 Risk Factor Due To „„KDIGO Guidelines suggest that an ARB or ACEI be used in diabetic adults with CKD and urine albumin excretion 30-300 mg/24 hours (or equivalent). (2D) Potassium intake Increased dietary potassium intake from Table 1. Acute Versus Chronic Hyperkalemia 3, 4 salt substitute, potassium-rich heart-healthy „„KDIGO Guidelines recommend that an ARB or ACEI be used in Emergency diagnostic Elective/etiologic diets, and herbal supplements both diabetic and nondiabetic adults with CKD and urine albumin workup:14 workup:14 Acute Hyperkalemia Chronic Hyperkalemia Metabolic acidosis Potassium shift from the intracellular to the excretion >300 mg/24 hours (or equivalent). (1B) extracellular space 1. A ssessment of cardiac function, 1. Comprehensive laboratory workup „„There is insufficient evidence to recommend combining an kidneys, and urinary tract Caused by abnormal net release of Caused by impairment of RAASi Treatment with ACEIs and ARBs block the ACEI with ARBs to prevent progression of CKD. (Not Graded) 2. Review of medication used potassium from cells, often due to potassium excretory process renin-angiotensin system and cause lower 2. Assessment of hydration status trauma, metabolic acidosis (depends and/or increased potassium load serum aldosterone ƒƒ Subsequent research shows that dual RAAS inhibition with ACEI on etiology), hemolytic states plus ARB not only fails to improve cardiovascular or renal outcomes, 3. Electrocardiogram 12 Diabetes Insulin deficiency and hypertonicity caused but predisposes patients to serious adverse events. by hyperglycemia contribute to an inability Requires immediate attention, ie, Requires ongoing management to disperse high acute potassium load into cardiac monitoring, acute medical to correct the underlying the intracellular space interventions, possibly dialysis disturbances in potassium balance, Considerations for using an ACEI or ARB in patients with CKD: ie, nonpharmacological and pharmacological interventions Heart failure Reduction in renal perfusion, use of RAASi or MRA „„Hyperkalemia and worsening kidney function can develop. Disclaimer: Information contained in this Management goals: induce Management goals: induce Coronary artery and Use of RAASi, oxidative stress, „„It is important to monitor serum potassium and estimated potassium redistribution and potassium redistribution peripheral vascular disease atherosclerosis glomerular filtration rate (eGFR) within several weeks of starting National Kidney Foundation excretion, restore normal and excretion to prevent the educational resource is based or escalating a RAASi.13 electrophysiology of the cell development or recurrence of upon current data available at the Advanced age Decreases in plasma renin activity and membrane, prevent cardiac hyperkalemia; monitor potassium time of publication. Information is arrhythmia intake through diet plasma aldosterone levels with age, as well „„Discontinuing these drugs is helpful in controlling or treating as frequent use of NSAIDS in this population. intended to help clinicians become hyperkalemia, but the disadvantage is that it increases the risk aware of new scientific findings and for kidney disease progression and cardiovascular events.6 developments. This clinical bulletin is not intended to set out a preferred Abbreviations: ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor standard of care and should not be blocker; MRA, mineralocorticoid receptor antagonist; NSAIDS, nonsteroidal anti-inflammatory drugs; RAASi, renin-angiotensin-aldosterone system inhibitors. construed as one. Neither should the information be interpreted as prescribing an exclusive course of management. TREATMENT OF HYPERKALEMIA IN CKD REFERENCES The steps to address hyperkalemia include stabilization + redistribution, and excretion/removal of potassium. 1. T ran HA. Extreme hyperkalemia. 11. Ink er LA, Astor BC, Fox CH, et al. KDOQI U.S. Best Practices in Managing South Med J. 2005;98:729-732. commentary on the 2012 KDIGO clinical Table 3. Summary of interventions used for acute or chronic treatment of hyperkalemia6 practice guideline for the evaluation and K 2. Gum z ML, Rabinowitz L, Wingo CS. An HYPERKALEMIA integrated view of potassium homeostasis. management of CKD. Am J Kidney Dis. May Treatment Route of Onset/ Mechanism Comments N Engl J Med. 2015;373:60-72. 2014;63(5):713-735. in Chronic Kidney Disease administration duration 3. Alv o M, Warnock DG. Hyperkalemia. 12. Mer cier K, Smith H, Biederman J. Renin- West J Med. 1984;141:666-671. angiotensin-aldosterone system 6.8 mmol of calcium, Intravenous (acute) 1-3 min Membrane „„ Does not affect serum potassium level inhibition: overview of the therapeutic 4. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of corresponding to 10 ml CaCl 30-60 min potential „„ Effect measured by normalization of electrocardiographic changes use of angiotensin-converting enzyme (10%)* or 30 ml calcium gluconate stabilization „„ Dose can be repeated if no effects noted hyperkalemia and its significance in chronic kidney inhibitors, angiotensin receptor blockers, (10%) solutions „„ Caution advised in patients receiving digoxin disease. Arch Intern Med. 2009;169:1156-1162. mineralocorticoid receptor antagonists, 50-250 ml hypertonic saline (3-5%)** Intravenous (acute) 5-10 min Membrane „„ Efficacy only in hyponatremic patients 5. Jain N, Kotla S, Little BB, et al. Predictors of and direct renin inhibitors. Prim Care. ~2 h potential stabilization hyperkalemia and death in patients with 2014;41:765-778. cardiac and renal disease. Am J Cardiol. 50-100 mmol sodium bicarbonate Intravenous (acute) 5-10 min Redistribution „„ Sodium may worsen pre-existing hypertension and heart failure 13. V assalotti JA, Centor R, Turner BJ, et al; U.S. 2012;109:1510-1513. or oral (chronic) ~2 h „„ Efficacy questioned for acute treatment of patients on dialysis Kidney Disease Outcomes Quality Initiative 6. K ovesdy CP. Management of hyperkalaemia (KDOQI). A practical approach to detection 10 units of regular insulin Intravenous (acute) 30 min Redistribution „„ Administer with 50 g of glucose intravenously to prevent hypoglycemia in chronic kidney disease. Nat Rev Nephrol. and management of chronic kidney disease 4-6 h 2014;10:653-662. for the primary care clinician [Epub ahead of ß2-receptor agonists: Intravenous or 30 min Redistribution „„ Effect independent of insulin and aldosterone 7. Sar afidis PA, Blacklock R, Wood E, et al. print September 18 2015]. Am J Med. 2015. 10-20 mg aerosol (nebulized) or nebulized 2-4 h „„ Caution in patients with known coronary artery disease Prevalence and factors associated with 0.5mg in 100ml of 5% dextrose (both acute) 14. L ehnhardt A, Kemper MJ. Pathogenesis, in water (intravenous) hyperkalemia in predialysis patients followed in diagnosis, and management of a low-clearance clinic. Clin J Am Soc Nephrol. hyperkalemia. Pediatr Nephrol. March 40 mg furosemide or equivalent Intravenous (acute) Varies Excretion „„ Loop diuretics for acute intervention 2012;7:1234-1241. 2011;26:377-384. dose of other loop diuretic. Higher or oral (chronic) Until diuresis „„ Loop or thiazide diuretics for chronic management; loop diuretic for GFR <40 ml/min/1.73 m2 15 8. T urgut F, Balogun RA, Abdel-Rahman 15. Sar afidis PA, Georgianos PI, Bakris GL. doses may be needed in patients present or „„ May not be effective in patients with reduced GFR EM. Renin-angiotensin-aldosterone system with advanced CKD longer Advances in treatment of hyperkalemia blockade effects on the kidney in the elderly: in chronic kidney disease. Expert Opin Fludrocortisone acetate ≥0.1 mg Oral (chronic) NA Excretion „„ In patients with aldosterone deficiency, large doses might be needed to effectively lower benefits and limitations. Clin J Am Soc Pharmacother. 2015;16:2205-2215. (up to 0.4-1.0 mg daily) potassium levels Nephrol. 2010;5:1330-1339. „„ Sodium retention, edema, and hypertension might occur, and acceleration of kidney and 16. U .S. Food and Drug Administration (FDA). cardiovascular disease 9. Xie X, Liu Y, Perkovic V, et al. Renin-angiotensin Kayexalate. http://www.accessdata.fda.gov/ system inhibitors and kidney and drugsatfda_docs/label/2011/011287s023lbl. Cation exchange resins Sodium Oral or rectal (either 1-2 h Excretion „„ Cases of intestinal necrosis, which may be fatal, and other serious GI adverse events have cardiovascular outcomes in patients with pdf. Updated December 2010. Accessed polystyrene sulfonate 25-50 g acute or chronic), �4-6 h been reported16 CKD: a Bayesian Network meta-analysis of December 22 2015. with or without „„ May cause hypokalemia and electrolyte disturbances16 randomized clinical trials [Epub ahead of print sorbitol „„ Cannot be used in medical emergencies16 17. V eltassa® Prescribing Information. https:// ›› Hyperkalemia in Chronic Kidney Disease (CKD) 16 November 17 2015]. Am J Kidney Dis. 2015. „„ Caution in patients with heart failure due to sodium load www.veltassa.com/pi.pdf. Updated November ›› Treatment with RAAS Inhibitors (RAASi) in CKD 10. Kidne y Disease: Improving Global Outcomes Cation exchange polymer Oral (either acute 7 h Excretion „„ Should not be used as an emergency treatment for life-threatening hyperkalemia 2016. Accessed April 14 2017. (KDIGO) CKD Work Group. KDIGO 2012 ›› Diagnosis and Evaluation of Hyperkalemia Patiromer 8.4, 16.8, or 25.2 g or chronic) ~48 h because of its delayed onset of action17 „„ There are no restrictions regarding concomitant use of patiromer with immediate- clinical practice guideline for the evaluation ›› Treatment of Hyperkalemia in CKD acting emergency treatments for hyperkalemia and management of chronic kidney disease. „„ Risks include worsening of gastrointestinal motility and hypomagnesemia17 Kidney Int Suppls. 2013;3:1-150. „„ The most common Adverse Reactions in clinical trials were constipation, hypomagnesemia, diarrhea, nausea, abdominal discomfort and flatulence17 Dialysis Hemodialysis Within minutes Removal „„ Effects of dialysis on serum sodium, bicarbonate, calcium and/or magnesium levels can (acute or chronic); until end of affect results This publication has been sponsored and Peritoneal dialysis dialysis or „„ For chronic hemodialysis, missed treatments and 2-day interdialytic interval may have developed in collaboration with Relypsa, Inc. (chronic) longer*** a negative impact on outcomes.

30 East 33rd Street *CaCl is caustic and could damage peripheral veins. **Limited data available from clinical studies. ***Effects can last for an unspecified length of time, depending on ongoing potassium intake or cellular New York, NY 10016 redistribution. Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; GI, gastrointestinal; NA, not applicable. | Adapted with permission from Kovesdy CP. Management of hyperkalaemia 800.622.9010 in chronic kidney disease. Nat Rev Nephrol, 2014;10:659-662. Copyright 2014 by Macmillan Publishers Limited. www.kidney.org © 2016 National Kidney Foundation, Inc. 02-10-7259_DBH TREATMENT OF HYPERKALEMIA IN CKD REFERENCES The steps to address hyperkalemia include stabilization + redistribution, and excretion/removal of potassium. 1. T ran HA. Extreme hyperkalemia. 11. Ink er LA, Astor BC, Fox CH, et al. KDOQI U.S. Best Practices in Managing South Med J. 2005;98:729-732. commentary on the 2012 KDIGO clinical Table 3. Summary of interventions used for acute or chronic treatment of hyperkalemia6 practice guideline for the evaluation and K 2. Gum z ML, Rabinowitz L, Wingo CS. An HYPERKALEMIA integrated view of potassium homeostasis. management of CKD. Am J Kidney Dis. May Treatment Route of Onset/ Mechanism Comments N Engl J Med. 2015;373:60-72. 2014;63(5):713-735. in Chronic Kidney Disease administration duration 3. Alv o M, Warnock DG. Hyperkalemia. 12. Mer cier K, Smith H, Biederman J. Renin- West J Med. 1984;141:666-671. angiotensin-aldosterone system 6.8 mmol of calcium, Intravenous (acute) 1-3 min Membrane „„ Does not affect serum potassium level inhibition: overview of the therapeutic 4. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of corresponding to 10 ml CaCl 30-60 min potential „„ Effect measured by normalization of electrocardiographic changes use of angiotensin-converting enzyme (10%)* or 30 ml calcium gluconate stabilization „„ Dose can be repeated if no effects noted hyperkalemia and its significance in chronic kidney inhibitors, angiotensin receptor blockers, (10%) solutions „„ Caution advised in patients receiving digoxin disease. Arch Intern Med. 2009;169:1156-1162. mineralocorticoid receptor antagonists, 50-250 ml hypertonic saline (3-5%)** Intravenous (acute) 5-10 min Membrane „„ Efficacy only in hyponatremic patients 5. Jain N, Kotla S, Little BB, et al. Predictors of and direct renin inhibitors. Prim Care. ~2 h potential stabilization hyperkalemia and death in patients with 2014;41:765-778. cardiac and renal disease. Am J Cardiol. 50-100 mmol sodium bicarbonate Intravenous (acute) 5-10 min Redistribution „„ Sodium may worsen pre-existing hypertension and heart failure 13. V assalotti JA, Centor R, Turner BJ, et al; U.S. 2012;109:1510-1513. or oral (chronic) ~2 h „„ Efficacy questioned for acute treatment of patients on dialysis Kidney Disease Outcomes Quality Initiative 6. K ovesdy CP. Management of hyperkalaemia (KDOQI). A practical approach to detection 10 units of regular insulin Intravenous (acute) 30 min Redistribution „„ Administer with 50 g of glucose intravenously to prevent hypoglycemia in chronic kidney disease. Nat Rev Nephrol. and management of chronic kidney disease 4-6 h 2014;10:653-662. for the primary care clinician [Epub ahead of ß2-receptor agonists: Intravenous or 30 min Redistribution „„ Effect independent of insulin and aldosterone 7. Sar afidis PA, Blacklock R, Wood E, et al. print September 18 2015]. Am J Med. 2015. 10-20 mg aerosol (nebulized) or nebulized 2-4 h „„ Caution in patients with known coronary artery disease Prevalence and factors associated with 0.5mg in 100ml of 5% dextrose (both acute) 14. L ehnhardt A, Kemper MJ. Pathogenesis, in water (intravenous) hyperkalemia in predialysis patients followed in diagnosis, and management of a low-clearance clinic. Clin J Am Soc Nephrol. hyperkalemia. Pediatr Nephrol. March 40 mg furosemide or equivalent Intravenous (acute) Varies Excretion „„ Loop diuretics for acute intervention 2012;7:1234-1241. 2011;26:377-384. dose of other loop diuretic. Higher or oral (chronic) Until diuresis „„ Loop or thiazide diuretics for chronic management; loop diuretic for GFR <40 ml/min/1.73 m2 15 8. T urgut F, Balogun RA, Abdel-Rahman 15. Sar afidis PA, Georgianos PI, Bakris GL. doses may be needed in patients present or „„ May not be effective in patients with reduced GFR EM. Renin-angiotensin-aldosterone system with advanced CKD longer Advances in treatment of hyperkalemia blockade effects on the kidney in the elderly: in chronic kidney disease. Expert Opin Fludrocortisone acetate ≥0.1 mg Oral (chronic) NA Excretion „„ In patients with aldosterone deficiency, large doses might be needed to effectively lower benefits and limitations. Clin J Am Soc Pharmacother. 2015;16:2205-2215. (up to 0.4-1.0 mg daily) potassium levels Nephrol. 2010;5:1330-1339. „„ Sodium retention, edema, and hypertension might occur, and acceleration of kidney and 16. U .S. Food and Drug Administration (FDA). cardiovascular disease 9. Xie X, Liu Y, Perkovic V, et al. Renin-angiotensin Kayexalate. http://www.accessdata.fda.gov/ system inhibitors and kidney and drugsatfda_docs/label/2011/011287s023lbl. Cation exchange resins Sodium Oral or rectal (either 1-2 h Excretion „„ Cases of intestinal necrosis, which may be fatal, and other serious GI adverse events have cardiovascular outcomes in patients with pdf. Updated December 2010. Accessed polystyrene sulfonate 25-50 g acute or chronic), �4-6 h been reported16 CKD: a Bayesian Network meta-analysis of December 22 2015. with or without „„ May cause hypokalemia and electrolyte disturbances16 randomized clinical trials [Epub ahead of print sorbitol „„ Cannot be used in medical emergencies16 17. V eltassa® Prescribing Information. https:// ›› Hyperkalemia in Chronic Kidney Disease (CKD) 16 November 17 2015]. Am J Kidney Dis. 2015. „„ Caution in patients with heart failure due to sodium load www.veltassa.com/pi.pdf. Updated November ›› Treatment with RAAS Inhibitors (RAASi) in CKD 10. Kidne y Disease: Improving Global Outcomes Cation exchange polymer Oral (either acute 7 h Excretion „„ Should not be used as an emergency treatment for life-threatening hyperkalemia 2016. Accessed April 14 2017. (KDIGO) CKD Work Group. KDIGO 2012 ›› Diagnosis and Evaluation of Hyperkalemia Patiromer 8.4, 16.8, or 25.2 g or chronic) ~48 h because of its delayed onset of action17 „„ There are no restrictions regarding concomitant use of patiromer with immediate- clinical practice guideline for the evaluation ›› Treatment of Hyperkalemia in CKD acting emergency treatments for hyperkalemia and management of chronic kidney disease. „„ Risks include worsening of gastrointestinal motility and hypomagnesemia17 Kidney Int Suppls. 2013;3:1-150. „„ The most common Adverse Reactions in clinical trials were constipation, hypomagnesemia, diarrhea, nausea, abdominal discomfort and flatulence17 Dialysis Hemodialysis Within minutes Removal „„ Effects of dialysis on serum sodium, bicarbonate, calcium and/or magnesium levels can (acute or chronic); until end of affect results This publication has been sponsored and Peritoneal dialysis dialysis or „„ For chronic hemodialysis, missed treatments and 2-day interdialytic interval may have developed in collaboration with Relypsa, Inc. (chronic) longer*** a negative impact on outcomes.

30 East 33rd Street *CaCl is caustic and could damage peripheral veins. **Limited data available from clinical studies. ***Effects can last for an unspecified length of time, depending on ongoing potassium intake or cellular New York, NY 10016 redistribution. Abbreviations: CKD, chronic kidney disease; GFR, glomerular filtration rate; GI, gastrointestinal; NA, not applicable. | Adapted with permission from Kovesdy CP. Management of hyperkalaemia 800.622.9010 in chronic kidney disease. Nat Rev Nephrol, 2014;10:659-662. Copyright 2014 by Macmillan Publishers Limited. www.kidney.org © 2016 National Kidney Foundation, Inc. 02-10-7259_DBH