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HYPERKALAEMIA challenge in CKD

Hyperkalaemia is a highly prevalent condition in your patients with chronic kidney disease1 and can jeopardise their beneficial RAASi therapy2,3

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RAASi therapy is vital

Progression of CKD to kidney failure, the avoidance or delay in initiating dialysis therapy, and the risks associated with dialysis are critically important to patients.4

  • RAASi have been shown to slow kidney function decline more effectively than other blood pressure-lowering drugs and to reduce proteinuria.4-6

RAASi are the cornerstone of therapy in CKD, and their use at the highest tolerated dose is recommended by multiple organisations4,7

  • Two landmark trials (IDNT8: Irbesartan Diabetic Nephropathy Trial and RENAAL9: Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) were conducted in patients with T2DM and CKD with albuminuria >1 g/d.
  • The renoprotective effect of these drugs was evidenced by a 
    16–20% reduction in the composite endpoint of risk of death, progression to dialysis or doubling for serum creatinine.4,8,9
  • Ramipril use in patients with non-diabetic nephropathy has also been shown to have a renoprotective effect, reducing both proteinuria and the rate of GFR decline.10

IDNT and RENAAL: reduced risk of death, ESRD, or doubling of serum creatinine concentration with RAASi8,9

IDNT8

Diagram: two key trials show better outcomes in CKD with RAASi

Patient population: 

1,715

Patients with diabetic nephropathy

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Treatment: 

Once daily irbesartan 300 mg, amlodipine 10 mg or placebo

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Primary endpoint: 

Composite of death, ESRD or doubling of
baseline serum creatinine

Mean follow-up: 

2.6

years

Risk reduction in primary endpoint:

20%

vs placebo
(p=0.02)

23%

vs amlodipine
(p=0.006)

RENAAL9

Diagram: two key trials show better outcomes in CKD with RAASi

Patient population: 

1,513

Patients with diabetic nephropathy

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Treatment: 

Once daily losartan 50−100 mg or placebo

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Primary endpoint: 

Composite of death, ESRD or doubling of
baseline serum creatinine

Mean follow-up: 

3.4

years

Risk reduction in primary endpoint:

16%

vs placebo
(p=0.02)

HYPERKALAEMIA risk is exacerbated by RAASi

Guideline-directed use of RAASi has been cited as a major factor in the development of hyperkalaemia in patients with CKD.11

  • In clinical trials, RAASi have been shown to increase the risk of hyperkalaemia in patients with CKD.12
  • Real-world studies consistently show an approximate 1.5-fold increased risk of hyperkalaemia in patients on RAASi,13,14 with risk increasing with severity of kidney disease.15

Proportion of patients with hyperkalaemia during the first year of therapy with RAASi increases with severity of kidney disease15

Bar chart: hyperkalaemia with RAASi increases with severity of CKD
Bar chart: hyperkalaemia with RAASi increases with severity of CKD

The impact of RAASi on the renin−angiotensin−aldosterone system

Diagram: impact of RAASi on renal function
Diagram: impact of RAASi on renal function
Proportion of patients with
hyperkalaemia
The impact of RAASi on the renin−
angiotensin−aldosterone system

HYPERKALAEMIA leads to suboptimal RAASi use

Current guidelines recommend dose reduction or discontinuation of RAASi if persistent hyperkalaemia is a problem in patients with CKD. As a result, hyperkalaemia is one of the main reasons for withholding RAASi treatment.2,3

  • In a large US database analysis,2 ~40% and ~50% of patients on maximum RAASi dose experiencing mild or moderate-to-severe hyperkalaemia, respectively, had their dose reduced or stopped after a hyperkalaemic event. 

Nearly half of patients on maximal RAASi dose have their treatment reduced or stopped after a hyperkalaemia event2

Mild hyperkalaemia: 38% of CKD patients stop/reduce RAASi post HK event
Mild hyperkalaemia: 38% of CKD patients stop/reduce RAASi post HK event
Mild hyperkalaemia: 38% of CKD patients stop/reduce RAASi post HK event

Nearly half of patients on maximal RAASi dose have their treatment reduced or stopped after a hyperkalaemia event2

Moderate/severe hyperkalaemia: 47% of CKD patients stop/reduce RAASi
Moderate/severe hyperkalaemia: 47% of CKD patients stop/reduce RAASi
Moderate/severe hyperkalaemia: 47% of CKD patients stop/reduce RAASi
Mild
hyperkalaemia
Moderate-to-severe
hyperkalaemia

However, reducing or stopping RAASi is associated with an increased risk of mortality and morbidity.2,16 

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Physicians, therefore, are often faced with the dilemma of using RAASi and accepting hyperkalaemia or reducing/stopping RAASi and accepting poorer clinical outcomes

What is needed is a therapy that allows CKD patients to stay on beneficial RAASi therapy with reliable long-term control of serum K+ levels.

Mortality risk doubles when RAASi is reduced or stopped2

Bar chart: mortality risk in CKD doubles when RAASi is reduced or stopped

Current treatment options for chronic HYPERKALAEMIA are limited

Both short- and long-term treatment strategies are critical for the management of hyperkalaemia.17 However, currently available options focus mainly on emergency and intermediate care,17 and there are substantial limitations associated with current treatment options for chronic hyperkalaemia:

Image: limited treatment options for chronic hyperkalaemia

Dietary modifications may lead to restricted consumption of healthy foods,18 and it may be very difficult for patients already on a restricted diet to adhere to further dietary modifications.19,20 The effects of dietary interventions on outcomes are uncertain.19

Image: limited treatment options for chronic hyperkalaemia

Non-K+-sparing loop diuretics depend on residual renal function and are associated with increased risk of gout and diabetes, volume contraction and reduced potassium excretion, and sarcopenia.17,21

Image: limited treatment options for chronic hyperkalaemia

Traditional K+-binders (SPS and CPS) can be associated with life-threatening GI side effects and hypokalaemia22,23 and may not be suitable in those who cannot tolerate an increase in sodium (SPS).23

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There is an unmet need for a reliable long-term option for the management of chronic hyperkalaemia that enables patients to continue RAASi therapy at target doses.17

References & footnotes

ACEi, angiotensin II converting enzyme inhibitor; ARB, angiotensin II-receptor blocker; CKD, chronic kidney disease; CPS, calcium polystyrene sulfonate; ESRD, end-stage renal disease; eGFR, estimated glomerular filtration rate; GI, gastrointestinal; HK, hyperkalaemia; IDNT, Irbesartan Diabetic Nephropathy Trial; K+, potassium ions; MRA, mineralocorticoid-receptor antagonist; Na+, sodium ions; NIDDM, non-insulin-dependent diabetes mellitus; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan; RAASi, renin−angiotensin−aldosterone system inhibitors; RR, relative risk; SPS, sodium polystyrene sulfonate; T2DM, type 2 diabetes mellitus; US, United States.

References:

1. Rosano GMC, et al. Eur Heart J Cardiovasc Pharmacother 2018;4(3):180−8. 2. Epstein M, et al. Am J Manag Care 2015;21(11 Suppl):S212−S220. 3. Yildirim T, et al. Ren Fail 2012;34(9):1095−9. 4. KDIGO Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int 2020;98(Suppl 4S):S1–S116. 5. KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl 2013;3:1–150. 6. National Kidney Foundation. K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. 2004. Available at: kidneyfoundation.cachefly.net/professionals/KDOQI/guidelines_bp/index.htm (accessed July 2020). 7. National Institute for Health and Care Excellence. Chronic kidney disease in adults: assessment and management. 2014. Available at: http://www.nice.org.uk/CG182 (accessed April 2020). 8. Lewis EJ, et al. N Engl J Med 2001;345(12):851−60. 9. Brenner BM, et al. N Engl J Med 2001;345(12):861−9. 10. The GISEN Group. Lancet 1997;28;349(9069):1857−63. 11. Palmer BF. N Engl J Med 2004;351(6):585−92. 12. Georgianos PI, Agarwal R. Kidney Int 2018;93(2):325−34. 13. Nilsson E, et al. Int J Cardiol 2017;245:277−84. 14. Einhorn LM, et al. Arch Intern Med 2009;169(12):1156−62. 15. Bandak G, et al. J Am Heart Assoc 2017;6(7):e005428. 16. Qiao Y, et al. JAMA Intern Med 2020;180(5):718−26. 17. Dunn JD, et al. Am J Manag Care. 2015;21(15 Suppl):S307−S315. 18. National Kidney Foundation. The DASH Diet. Available at: kidney.org/atoz/content/Dash_Diet (accessed July 2020). 19. Palmer SC, et al. Cochrane Database Syst Rev 2017;4:CD011998. 20. Vendramini LC, et al. Braz J Med Biol Res 2012;45(9):834−40. 21. Ishikawa S, et al. PLOS One 2018;13:1–16. 22. Calcium Resonium PI. Sanofi 2018. 23. Kayexalate® US PI. Sanofi 2017.