1. Hyperkalemia Management: Current Challenges and Evolving Perspectives
Murray Epstein, MD, FASN

2. RAASi Promotes Kidney-Saving and Life-Saving Benefits in Patients With CKD, Heart Failure, or Diabetes Mellitus
CKD, chronic kidney disease; RAASi, renin-angiotensin-aldosterone system inhibitor.

3. RALES/EMPHASIS-HF: MRAs Improved Survival in Patients With HF
HF, heart failure; MRAs, mineralocorticoid receptor antagonists.
Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):

4. Cumulative Kaplan–Meier Estimates of Rates of the Primary Outcome and Other Outcomes, According to Study Group
Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B: EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364(1):11-21.

5. Hyperkalemia Is a Common Complication in Patients With Heart Failure Receiving Mineralocorticoid Receptor Antagonists

6. Rate of Admission for Hyperkalemia (per 1,000 patients)
Hospitalizations for Hyperkalemia Spiked in Heart Failure Patients After Publication of RALES
Rate of hospital admission for hyperkalemia among patients recently hospitalized
for heart failure who were receiving ACEi 14
Online release
of RALES 12 10 8
Rate of Admission for Hyperkalemia (per 1,000 patients) 6 4 2
1994
1995
1996
1997
1998
1999
2000
2001
Study Year
The yellow lines and 95% CIs beginning in 1999 represent the projected rates of hospital admissions for hyperkalemia.
Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):

7. Hyperkalemia Is a Major Reason for Discontinuation of MRA
134 HF patients followed in a Portuguese HF clinic
Spironolactone use in patients with sCr ≤2.5 mg/dL and K+ ≤5 mEq/L
25% of patients withdrew from spironolactone therapy (19/76)
Reason for spironolactone suspension (%)
% of Patients
Discontinuation of MRA
*Severe hyperkalemia (≥6 mEq/L) occurred in 7 patients who withdrew from spironolactone therapy (9.2%).
HF, heart failure; MRA, mineralocorticoid receptor antagonist; sCR, serum creatinine
Lopes RJ, et al. Clin Cardiol. 2008;31:

8. EMPHASIS-HF Study Comment RAH
THELANCETDE-D S (14)
Embargo: Oct 24, 2014—00:01 (BST)
EMPHASIS-HF Study
Mineralocorticoid receptor antagonists: part of an emerging treatment paradigm for chronic kidney disease
Science Picture Co/Science Photo Library
The Global Burden of Disease 2010 study1 identified chronic kidney failure as one of the three causes of death with the greatest increase from 1990 to Patients with chronic kidney disease have up to 3·5 times increased risk of cardiovascular events,1 and cardiovascular disease is the most common cause of mortality and morbidity in patients with chronic kidney disease. Despite these sobering observations, there are few evidence-based treatments for patients with chronic kidney disease on haemodialysis.
Attention has increasingly focused on the use of the mineralocorticoid receptor antagonists spironolactone and eplerenone in the treatment of patients with chronic kidney disease, including those on haemodialysis.2 The rationale for prescribing mineralocorticoid receptor antagonists is compelling. The beneficial cardiovascular
In this issue of the The Lancet Diabetes & Endocrinology, Fujita and colleagues6 report the results of a prospective, double-blind, randomised, placebo-controlled trial of 314 hypertensive non-diabetic patients with albuminuria (urinary albumin-to-creatinine ratio [UACR] 30–599 mg/g) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers or both, who were randomly assigned to either low- dose eplerenone (50 mg/day) or placebo. Background standard antihypertensive treatment was continued to reach therapeutic goals (<130/80 mm Hg) for a treatment period of 52 weeks. The primary efficacy measure (percent reduction in UACR from baseline in the first morning void urine) was greater in the eplerenone group than the placebo group (between-group difference –27·6%, 95% CI
–51·15 to –3·96; p=0·0222).
Lancet Diabetes Endocrinol 2014
Published Online
October 24, S (14)
See Online/Articles S (14)

9. The Rationale for Prescribing MRA in Patients With CKD Is Compelling
Various experimental and clinical studies have implicated aldosterone, independent of angiotensin II, in the pathogenesis of CV and renal diseasea
The CV benefits of MRA have been attributed to several mechanismsb
- CV remodeling - Oxidative stress
- Collagen turnover - Endothelial function
“Most clinicians are reluctant to use mineralocorticoid receptor antagonists in patients with chronic kidney disease and in patients with end-stage renal disease on hemodialysis because of the risk of this important side-effect (hyperkalemia).”c
MRAs are contraindicated in patients with an eGFR<30 mL/min/1.73 m², including patients receiving hemodialysis3
CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; MRAs, mineralocorticoid receptor antagonists.
Epstein M. J Clin Hypertens (Greenwich). 2009;11(2):55-60.
Brown NJ. Nat Rev Nephrol. 2013;9:
Epstein M. Lancet Diabetes Endocrinol. 2014;2(12):

10. MRA, but Not ARB, Added to a Regimen Including Maximal ACEi, Provides Greater Renoprotection in Diabetic Nephropathy Despite a Similar Effect on BP
Study Design. Asterisks denote inpatient CTRC admission.
ARB, angiotensin receptor blocker; ACEi, angiotensin-converting
enzyme inhibition; BP, blood pressure; DN, diabetic nephropathy;
MRA, mineralocorticoid receptor antagonist; UACR, urine albumin-to-creatinine ratio.
Mehdi UF et al. J Am Soc Nephrol. 2009;20:

11. Mean Serum K+ Concentration Was Significantly Higher in MRA vs ARB
100 mg once daily (n = 26)
25 mg once daily (n = 27)
Hyperkalemia (serum K+ >6.0 mEq/L) occurred at least once in 2, 10, and 14 subjects in the placebo, ARB, and MRA groups, respectively
(MRA vs placebo, P < .001; losartan vs placebo, P < .009).
ARB, angiotensin receptor blocker; MRA, mineralocorticoid receptor antagonist.
Mehdi UF et al. J Am Soc Nephrol. 2009;20:

12. Hyperkalemia Will Remain an Issue With LCZ-696 PARADIGM Heart Failure Study
PARADIGM-HF selected a population at low risk for hyperkalemia prior to randomization
Excluded patients with eGFR <30 mL/min/1.73 m2
Excluded patients with serum potassium level of more than 5.2 mmol/L at screening (or more than 5.4 mmol/L at randomization)
Run-in phase on ACEi that excluded 6% of patients due to AE, then run-in phase on LCZ-696 that excluded another 6% of patients due to AE, which selected a population that would be at low risk for hyperkalemia
Hyperkalemia rates remained high in all patients despite carefully selected population
>5.5 mmol/L: 16.1% LCZ-696 versus 17.3% ACEi (P = .15)
>6.0 mmol/L: 4.3% LCZ-696 versus 5.6% ACEi (P = .007)
CV mortality benefit with LCZ-696 versus ACEi demonstrated in patients with eGFR ≥60 mL/min/1.73 m2 and <60 mL/min/1.73 m2
ACEi, angiotensin-converting enzyme inhibitor; AE, adverse event; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HF, heart failure.
McMurray J, et.al. N Engl J Med. 2014;371(11):

13. CATCH-22 Prescribe RAASi and Accept Presence of Hyperkalemia?
Hyperkalemia versus RAASi: The Catch-22 of Managing Diseases That Benefit From RAASi Therapy!!
Prescribe RAASi and Accept Presence of Hyperkalemia?
Avoid/Discontinue Proven RAASi Therapies?
CATCH-22
RAASi, renin-angiotensin-aldosterone system inhibitor.

14. “An extensive study of patients with CKD or heart failure who were treated with RAAS inhibitors revealed an incidence of hyperkalemia of 5%-10%”
Schrier RW. Nat Rev Nephrol. 2010;6:

15. Hyperkalemia Is a Leading Reason for Not Starting RAASi and the Major Reason for Discontinuation of RAASi in CKD
279 patients with CKD followed up for a mean of 22 months
Baseline mean eGFR was 33.3 mL/min/1.73m2 and the serum K+ was 4.73 mEq/L
% of Patients
These figures examine, by CKD stage, medication use in older patients with identified CKD. Among Part D patients with CKD and a diagnosis of diabetes or hypertension, 60 and 54 percent use a renin-angiotensin system (RAS) agent. As CKD stage increases (and estimated glomerular filtration rate, or eGFR, declines), the percentage of patients on RAS agents falls, whether or not they have underlying diabetes or hypertension.
(80 patients)
(51 patients)
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RAASi, renin-angiotensin-aldosterone system inhibitor.
Yildrim T, et al. Ren Fail. 2012;34(9):

16. Hyperkalemia Increases With Dual RAAS Blockade in Patients at High Risk for CV Events and/or ESRD
Rate of Hyperkalemia
(% of patients) a b c
K+ level
>5.5 ≥6
>6
Treatment
Ramipril
Telmisartan
Ramipril + Telmisartan
Placebo + ACE or ARB
Aliskiren + ACE or ARB
Losartan
Aliskiren + Losartan
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CV, cardiovascular; ESRD, end-stage renal disease; RAAS, renin-angiotensin-aldosterone system.
a. Yusuf S, et al; ONTARGET Investigators. N Engl J Med. 2008;358(15): b. Parving HH, et al; ALTITUDE Investigators. N Engl J Med. 2012;367(23): c. Persson F, et al; AVOID Investigators. Diabetes Care. 2010;33(11):

17. Current Guidelines Tend to Lessen the Use of Full Recommended Doses of Renin-Angiotensin-Aldosterone System Inhibitors Because of Concerns Related to Hyperkalemia

18. Guidelines Recommend RAASi Modifications at Various Serum K+ Levels
>6.0
Serum K+ (mEq/L)
NICEe: Stop RAASi if >6.0
KDIGO Guidelines do not provide recommendationsd
ACC/AHA,a ESC HF,b K/DOQIf: Reduce dose of/stop ACEi/ARB, AA if >5.5
>5.5
K/DOQIf: don’t start RAASi if > 5.0
NICEe: don’t start RAASi if >5.0
HFSA HFc: MRA not recommended >5.0
ACA/AHA HFa: Maintain MRA
>5.0
Serum K+ Threshold Before Change in RAASi Guideline Recommendation
MRA, mineralocorticoid receptor antagonist; RAASi, renin-angiotensin-aldosterone inhibitor.
Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e
McMurray JJ, et al. Eur Heart J. 2012;33(14):
Heart Failure Society of America, Lindenfeld J, et al. J Card Fail. 2010;16(6):e1-e194.
KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1).
National Institute for Health and Care Excellence (NICE) [UK]

19. hyperkalemia is top concern with use of RAASi medication**
Hyperkalemia Prevents Use of Guideline-Recommended RAASi Therapy to Delay Progression to ESRD
RAASi treatment
in CKD*
Kidney Disease Outcomes Quality Initiative, Guideline 11: Use of ACEis and ARBs in CKD
In general, highest tolerated doses of ACEi or ARB (RAASi) are recommended
If hyperkalemia develops, reduce dose of ACEi or ARB and/or discontinue the ACEi or ARB
~90% of nephrologists:
hyperkalemia is top concern with use of RAASi medication**
*Estimates based on data adapted from Treatment Algorithm Quantitative Study, June 2013, N = 386.
**Primary market research, April 2012.
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; ESRD, end-stage renal disease; RAASi, renin-angiotensin-aldosterone system inhibitor.

20. Conclusions
RAASis confer substantive benefits including reducing cardiovascular events and retarding progression of renal disease in several disease states, including CHF, CKD, and diabetes mellitus
Hyperkalemia will remain an issue with newly introduced drugs such as Neprolysin inhibitors (LCZ-696)—PARADIGM Heart Failure Study
Hyperkalemia complicates the management of patients with ESRD who are undergoing hemodialysis
The wide gap between RAASis prescribing guidelines and reality—is hyperkalemia the reason?
As a consequence, we need effective and safe treatments to control hyperkalemia and facilitate treatment with optimal recommended doses of RAASis
CHF, congestive heart failure; CKD, chronic kidney disease; ESRD, end-stage renal disease; RAASis, renin-angiotensin-aldosterone inhibitors.