Correspondence

Hyperkalemia and Inhibitors of the Renin–Angiotensin–Aldosterone System

N Engl J Med 2004; 351:2450-2451December 2, 2004

Article

To the Editor:

In his excellent review, Palmer (Aug. 5 issue)1 discusses strategies for minimizing the incidence and degree of hyperkalemia in patients taking inhibitors of the renin–angiotensin–aldosterone system.2 One strategy he does not suggest is earlier initiation of therapy. The cardioprotective effects of aldosterone antagonists and the renoprotective effects of angiotensin-converting–enzyme (ACE) inhibitors (and angiotensin-receptor blockers) in patients with advanced disease have become clear. Earlier initiation of treatment, before the glomerular filtration rate and the ability to secrete potassium begin to decrease, would both slow the progression of disease and minimize the development of hyperkalemia. It is therefore tempting to speculate that starting these drugs at the onset of disease — when the margin between the therapeutic window and the threshold of toxicity is widest — could increase the overall benefits for patients while minimizing the major limitations of therapy for a longer time than would otherwise be possible. In addition to adaptive mechanisms,3 such considerations support the notion that these protective agents should be started as soon as disease (e.g., hypertension or type 2 diabetes mellitus) develops or at least before there is any clinically measurable evidence that renal injury has already begun.

Alan Segal, M.D.
University of Vermont College of Medicine, Burlington, VT 05401
alan.segal@uvm.edu

3 References

1. 1

   Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004;351:585-592
   Full Text | Web of Science | Medline

2. 2

   Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-551
   Full Text | Web of Science | Medline

3. 3

   Gennari FJ, Segal AS. Hyperkalemia: an adaptive response in chronic renal insufficiency. Kidney Int 2002;62:1-9
   CrossRef | Web of Science | Medline

Author/Editor Response

Initiating treatment at early stages of chronic kidney disease is of critical importance in addressing the growing burden of end-stage renal disease. The use of ACE inhibitors or angiotensin-receptor blockers to slow the progression of renal disease in patients with diabetes and microalbuminuria is generally not limited by the development of hyperkalemia, since renal function is typically well preserved. Whether the administration of these drugs should be initiated when there is not clinically measurable evidence of renal disease is an important question to consider. One could not justify treating all patients with diabetes for the sole purpose of renal protection, since nephropathy develops in fewer than half of them.1 On the other hand, these drugs have been shown to reduce the risk of cardiovascular events in patients with diabetes.2,3 Furthermore, both ACE inhibitors and angiotensin-receptor blockers delay the onset of clinical diabetes in patients at increased risk for cardiovascular disease, raising the possibility that therapy initiated in patients who are at risk only for diabetes could have a cardiovascular benefit.2-4 Clinical trials involving patients with glucose intolerance are currently being conducted to assess this possibility.5

Biff F. Palmer, M.D.
University of Texas Southwestern Medical School, Dallas, TX 75390-8856
biff.palmer@utsouthwestern.edu

5 References

1. 1

   American Diabetes Association. Nephropathy in diabetics. Diabetes Care 2004;27:Suppl:S79-S83
   CrossRef | Medline

2. 2

   Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:253-259
   CrossRef | Web of Science | Medline

3. 3

   Lindholm LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002;359:1004-1010
   CrossRef | Web of Science | Medline

4. 4

   Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004;363:2022-2031
   CrossRef | Web of Science | Medline

5. 5

   Prisant LM. Preventing type II diabetes mellitus. J Clin Pharmacol 2004;44:406-413
   CrossRef | Web of Science | Medline