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Aldosterone receptor blockade in chronic kidney disease.

Lene Boesby

Summary

This thesis considers the use of the selective aldosterone receptor inhibitor eplerenone in treatmentof patients with CKD and investigates the usability in CKD of AASI, a novel index of arterialstiffness. Aldosterone induces vascular inflammation and fibrosis leading to increased vesselstiffness. Surrogate markers of disease progression have been examined.

In patients with CKD cardiovascular morbidity and mortality is disproportionately high. Thereasons for this have not been fully elucidated. Arterial stiffness is increased in CKD and is due toaccelerated atherosclerosis and arteriosclerosis.

Worldwide, there has been a steady increase in the population of patients in need of renalreplacement therapy. In Denmark, the annual number of new end-stage CKD patients seems to havestabilized but the degree of co-morbidity has increased4.

Aldosterone induces fibrosis and inflammation in renal and systemic tissues, including vessels.The result of this is stiffer arteries, leading to greater risk of stroke and myocardial infarction. Stiffer renal arteries also lead to proteinuria. Information on arterial stiffness and proteinuriacan beobtained quite easily in the individual, with reliable and reproducible methods. Three clinicalstudies were completed, two interventional and one observational.

The initial study was a randomized cross-over design investigating the effect of eplerenone onalbuminuria in patients with non-diabetic CKD stage 1-4. It showed a reduced albumin excretionduring eplerenone treatment that was independent of concurrent decreases in blood pressure andkidney function (I14).

The second study (II25) investigated the reproducibility, usability and determinants of a novelindex of arterial stiffness in CKD named the ambulatory arterial stiffness index (AASI). It is derived from plots of individual 24 hour ambulatory blood pressure measurements. The diastolicblood pressure is plotted against the systolic blood pressure and the regression slope subtracted from one – this is defined as AASI. The result of compliant arteries is a steep slope, and low AASI .If on the other hand the slope is low, then AASI will be high and reflect stiffer arteries. Reference values have not yet been established. In the study it was found that AASI had moderate reproducibility in pre-dialysis patients with CKD stage 2-5. A good correlation between aortic PWVand AASI was found, whereas the correlation with AIx was poor. It was not possible to confirm acorrelation between AASI and kidney function.

The second interventional study in a randomized, open, parallel group design in CKD stage 3-4investigated the effect of eplerenone on measures of arterial stiffness after treatment for 24 weeks(III24). There was no effect on aortic PWV, but the AIx increased only in the control group,suggesting that reverse remodelling with eplerenone was possible in the resistance vessels.Albuminuria was also reduced, in line with results from study I14.

Altogether the studies show that eplerenone influences the condition of the arteries and reducesalbumin excretion. The mechanisms cannot be elucidated in these clinical studies. Eplerenone waswell tolerated in a diverse population of patients with CKD stage 1-4 in two studies. There were noserious events of hyperkalaemia or hypotension.

The novel index AASI has acceptable reproducibility essential in prospective studies and itcorrelates well with established measures of arterial stiffness, the aortic PWV. The determinants ofAASI in CKD are as in other populations primarily age and nightly blood pressure fall.