NDT Advance Access originally published online on July 5, 2006
Nephrology Dialysis Transplantation 2006 21(11):3343-3344; doi:10.1093/ndt/gfl371
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MR blockade in patients with chronic renal disease—not the more the merrier, but the earlier the better
Email: marcus.quinkler{at}charite.deSir,
We read with interest the recent review by Covic and coworkers [1], which highlights the possible role of spironolactone therapy in dialysis patients and summarizes the current literature. One of the major goals of spironolactone treatment in dialysis patients is the reduction of cardiomyopathy and cardiovascular morbidity and mortality. One of the major risks of spironolactone treatment is hyperkalaemia, as pointed out by the authors. The risk of hyperkalaemia correlates with the increase of the spironolactone dose. This pattern resembles the anti-androgenic effect of spironolactone (gynaecomastia, decreased libido and erectile dysfunction in men, and menstrual disturbances and mastodynia in women), which is weak at low doses and increases with higher doses (incidence of gynaecomastia with 50 mg spironolactone 6.9 and 52% at 150 mg daily) [2].
The doses of spironolactone in the treatment of primary hyperaldosteronism decreased from 200–400 mg in the 1970s and 80s to 12.5–50 mg daily in recent years. It has been shown that doses of 12.5–50 mg are often as effective as higher doses and in the treatment of therapy-resistent hypertension [3,4]. The new mineralocorticoid eplerenone requires higher doses than spironolactone, due to its lower potency, but it lacks the anti-androgenic side effects.
We share the opinion with the authors that spironolactone treatment in low doses and under tight supervision and control is possible in dialysis patients and might reduce their cardiac morbidity and mortality. Therefore, large numbers of trials are urgently needed.
However, we would like to emphasize the possible benefit of an anti-mineralocorticoid treatment at an earlier stage of renal disease, when the kidneys could profit from this treatment as well as the heart. Apart from deleterious effects on the heart, it is known that activation of the mineralocorticoid receptor (MR) also contributes to kidney damage in experimental models of hypertension. In hypertensive rats, aldosterone treatment induces severe vascular and glomerular sclerosis, fibrinoid necrosis and thrombosis. In addition, it causes interstitial leucocyte infiltration, tubular damage and results in an increase in albuminuria and pro-inflammatory molecules [5]. Administration of MR blockers or aldosterone ablation by adrenalectomy attenuates renal injury, reduces albuminuria and renal expression of proinflammatory molecules in rats independent of blood pressure reduction [5–7]. These observations support the renoprotective effects of MR antagonism in nephropathy. In humans, preliminary data suggest that spironolactone decreases proteinuria in patients with chronic renal disease and those with type 2 diabetes mellitus and early nephropathy [8–11].
We analysed renal biopsies of a large cohort of nearly 100 patients with chronic renal disease [12]. Patients with heavy albuminuria presented with high macrophage chemoattractant protein-1 expression and urinary excretion, with high macrophage invasion, with a high index of chronic damage and the worst renal survival. This group showed a significant 5-fold increase in mineralocorticoid receptor expression and a significant increase in inflammatory mediators such as transforming growth factor-ß1 and interleukin-6 [12]. Our data strongly support animal data linking aldosterone–MR activation to renal inflammation and proteinuria. Further studies are urgently required to assess the potential beneficial effects of MR antagonism in patients with renal disease. However, hyperkalaemia has been raised as a potential deleterious side effect, particularly in patients with reduced renal function, heart failure or diabetes [13,14], but careful titration [15] and the use of lower doses of MR antagonists minimizes this risk. Therefore, there is now an obvious need for larger trials with anti-mineralocorticoid treatment in patients with chronic renal disease as well as end-stage renal failure.
Conflict of interest statement. None declared.
1Department of Nephrology
Campus Virchow
2Division of Clinical Endocrinology
Campus Mitte
Charité Universitätsmedizin Berlin
Berlin, Germany
References
- Covic A, Gusbeth-Tatomir P, Goldsmith DJA. (2006) Is it time for spironolactone therapy in dialysis patients? Nephrol Dial Transplant 21:854–858.
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[Abstract/Free Full Text] - Levy DG, Rocha R, Funder JW. (2004) Distinguishing the antihypertensive and electrolyte effects of eplerenone. J Clin Endocrinol Metab 89:2736–2740.
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