Introduction Early stage chronic kidney disease (CKD) is a common condition affecting approximately 10% of the population and is associated with a high risk of adverse cardiovascular events. Activation of the renin–angiotensin–aldosterone system in CKD exerts adverse effects upon the cardiovascular system despite treatment with ACE inhibitors and angiotensin receptor blockers, a concept known as “aldosterone escape”. We hypothesised that cardiovascular abnormalities were present in early CKD and might be improved by the addition of the aldosterone antagonist spironolactone to standard treatments.
Methods 117 with stage 2 and 3 CKD, controlled hypertension (<130/85 mm Hg) and no history of cardiovascular disease or diabetes were recruited into a double-blind placebo controlled trial. Baseline clinical, echocardiography and cerebral metabolic rate parameters were compared with 40 healthy controls. Patients received an active 4-week run- in of spironolactone 25 mg daily, and were then randomly assigned to continue this treatment or receive placebo for a further 36 weeks. Left ventricular function (systolic, diastolic, myocardial deformation, elastance) and arterial stiffness/distensibilty were assessed before run-in and after 40 weeks of treatment using echocardiography, applanation tonometry and cerebral metabolic rate.
Results Patients with CKD had normal conventional indices of systolic function (ejection fraction, systolic tissue Doppler velocities) but reduced regional and global myocardial deformation (peak strain −15% ± 4 vs −17% ± 3, p<0.01, peak strain rate −0.88 s−1 ± 0.16 vs −1.06 s−1 ± 0.31, p<0.05) and impaired diastolic relaxation (E/Em 7.7 ± 2.1 vs 5.6 ± 1.1, p<0.01) compared with controls. The arterial–ventricular coupling ratio was maintained in both patients and controls, although the absolute values for arterial, left ventricular end-systolic and left ventricular end-diastolic elastances (p<0.05) were increased in CKD and were all inversely correlated with the glomerular filtration rate (r = −0.25, p<0.05). Spironolactone resulted in significant improvements in left ventricular mass (−14 g ± 13 vs +3 g ± 11, p<0.01), arterial and ventricular elastance (p<0.05) and myocardial deformation (global peak strain 2.5% ± 3.2 vs 0.2% ± 2.6, p<0.01, global peak strain rate 0.17 ± 0.32 vs 0.01 ± 0.22, p<0.05) without alteration in ejection fraction or systolic tissue velocities. Measurements of arterial stiffness were also improved (pulse wave velocity −0.8 m/s ± 1.0 vs −0.1 m/s ± 0.9, p<0.01, aortic distensibility 0.69 ± 0.86 × 10−3 mm Hg vs 0.04 ± 1.04 × 10−3 mm Hg, p<0.01). Systolic pressures were reduced with spironolactone but were not independent predictors of the change in left ventricular mass or any echocardiography parameter in multivariate regression models.
Conclusion Abnormalities of cardiovascular structure and function are present in asymptomatic individuals with early CKD without clinical evidence of heart or vascular disease. Treatment with spironolactone improved prognostic markers of cardiovascular function and provides support for a clinical outcome trial.