Correspondence
Spironolactone and ACE Inhibition in Chronic Renal Failure
N Engl J Med 2002; 346:456-457February 7, 2002
- Article
To the Editor:
I am surprised that the authors of the letter entitled “Spironolactone in Addition to ACE Inhibition to Reduce Proteinuria in Patients with Chronic Renal Disease” (Sept. 20 issue)1 concluded that the reduction in proteinuria seen after the administration of 25 mg of spironolactone per day “could not be explained by an effect of blood pressure, since there was no significant difference in blood pressure before and after the administration of spironolactone.”
In each of their eight patients, the mean blood pressure (calculated as systolic pressure + [0.67 × diastolic pressure]) was lower after treatment than before treatment, the mean (±SE) change being 10±1.76 mm Hg. It is well established that a reduction in mean blood pressure can produce a reduction in proteinuria.
The authors' thesis would have been more convincing if they had shown that proteinuria increased when spironolactone was discontinued without any accompanying change in arterial pressure.
1 ReferencesFranklin H. Epstein, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215
fepstein@caregroup.harvard. edu 1
Chrysostomou A ,Becker G . Spironolactone in addition to ACE inhibition to reduce proteinuria in patients with chronic renal disease. N Engl J Med 2001;345:925-926
Full Text | Web of Science | Medline
To the Editor:
In considering the beneficial effects of spironolactone and angiotensin-converting–enzyme (ACE) inhibition on proteinuria in patients with chronic renal disease, it is important to examine the effects on serum potassium levels. Although the risk of hyperkalemia in patients with chronic renal failure is low until the glomerular filtration rate is less than 5 ml per minute, there is a group of patients in whom hyperkalemia can develop before renal failure is so advanced; this group includes the growing population of patients with diabetes and hyporeninemic hypoaldosteronism. The hyperglycemia that is common among such patients and the salt restriction that is typically recommended to them can also predispose them to hyperkalemia.
We are afraid that the problem would grow if these treatment recommendations were extended to patients with chronic renal disease, even if the intention were to reduce proteinuria. We wish to emphasize the importance of close monitoring of serum potassium levels in these patients.
Jaume Almirall, M.D.
Thaïs Lopez, M.D.
Corporaciò Parc Taulí, 08208 Sabadell, Barcelona, Spain
jalmirall@cspt.es Author/Editor Response
The authors reply:
To the Editor: We thank Dr. Epstein for pointing out the difference in mean blood pressure, which, unfortunately, we had not calculated. Certainly we would not have expected spironolactone to be such an effective antihypertensive agent, but we acknowledge that its effect on blood pressure could have contributed to its antiproteinuric effect. In a meta-analysis of the effect of blood-pressure–lowering agents on proteinuria (41 studies, 1124 patients), Gansevoort et al.1 reported that a similar decrease in mean blood pressure (11.4 percent) was associated with a reduction of 17 percent in proteinuria if agents other than ACE inhibitors were given, whereas ACE inhibitors (leading to a 12 percent reduction in blood pressure) resulted in a 39.9 percent reduction in proteinuria, suggesting that there is a specific blood-pressure–independent effect of interfering with the renin–angiotensin–aldosterone pathway. In future studies of the effect of aldosterone antagonism on proteinuria, specific attention will have to be paid to the effect on the renin–angiotensin–aldosterone pathways and blood pressure.
We also appreciate the comments from Drs. Almirall and Lopez. In our group of patients, the serum potassium level did rise after the addition of spironolactone, but it remained in the normal range. This finding is consistent with those of the Randomized Aldactone Evaluation Study.2
Although patients with diabetes may have hyporeninemic hypoaldosteronism, it is not known whether the presence of this condition would militate against the therapeutic benefit of aldosterone-receptor blockade. Until recently, it has been believed that the adrenal cortex was the only site of mineralocorticoid production. Studies indicate that aldosterone synthesis occurs at extrarenal sites, including the endothelium and smooth-muscle cells.3 There is also evidence that the aldosterone response can be dissociated from circulating aldosterone levels.4,5 We agree that spironolactone should only be added to ACE inhibitor therapy with great caution in patients with renal impairment, since there is a risk of hyperkalemia that may be exacerbated by concomitant hyporeninemic hypoaldosteronism.
5 ReferencesAnastasia Chrysostomou, B.M., B.S.
Gavin Becker, M.D., M.B., B.S.
Royal Melbourne Hospital, Parkville 3052, Australia
anastasiac@optusnet.com. au 1
Gansevoort RT ,Sluiter WJ ,Hemmelder MH ,de Zeeuw D ,de Jong PE . Antiproteinuric effect of blood-pressure-lowering agents: a meta-analysis of comparative trials. Nephrol Dial Transplant 1995;10:1963-1974
Web of Science | Medline2
Pitt B ,Zannad F ,Remme WJ , et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-717
Full Text | Web of Science | Medline3
Hatakeyama H ,Miyamori I ,Fujita T ,Takeda Y ,Takeda R ,Yamamoto H . Vascular aldosterone: biosynthesis and a link to angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem 1994;269:24316-24320
Web of Science | Medline4
Takeda Y ,Miyamori I ,Inaba S , et al. Vascular aldosterone in genetically hypertensive rats. Hypertension 1997;29:45-48
Web of Science | Medline5
Brown NJ ,Nakamura S ,Ma L , et al. Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int 2000;58:1219-1227
CrossRef | Web of Science | Medline
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