Eplerenone, Sodium restriction, hydroChlorothiazide, and ACE-inhibition in Proteinuria Evaluated.

In many diabetic nephropathy patients loss of renal function occurs
despite treatment with angiotensin-converting enzyme inhibitors (ACEi)
or angiotensin receptor blockers (ARB), which is therapy of choice.
Aldosterone, that besides sodium and water retention promotes renal
inflammation and fibrosis, increases during ACEi and ARB ("aldosterone
escape") which may explain the incomplete renoprotection during these
therapies. Aldosterone levels can further increase when the
antihypertensive and antiproteinuric effects of ACEi or ARB are
potentiated by volume depletion with dietary sodium restriction and/or
diuretic treatment.
Mineralocorticoid receptor blockers (MRB; i.e. spironolactone and
eplerenone) inhibit the harmful effects of aldosterone, and MRB added to
ACEi or ARB effectively reduce proteinuria, hypertension, and renal
function decline.
Whether the added benefits of MRB on top of ACEi or ARB result from
either the diuretic or the antifibrotic properties of MRB, is unknown.
Furthermore, very few studies in renal patients investigated the
protective effects of eplerenone, which is a relatively new but
promising agent since it acts selectively and therefore has the benefit
over spironolactone (a non-selective MRB) of less/no antiandrogenic and
progestational side effects.
Therefore we aim to study: 1. whether the renoprotective effects of
ACEi, with and without volume depletion measures, can be improved by the
addition of eplerenone, 2. whether the renoprotective effects of
eplerenone added to ACEi outweigh the renoprotective effects of the
diuretic hydrochlorothiazide added to ACEi; in patients with diabetic
nephropathy.

Objectives:

1. To investigate the added effects of eplerenone on top of ACEi, with and without dietary sodium restriction, on residual albuminuria, hypertension, and tubular injury markers, in patients with diabetic nephropathy;

2. To investigate whether the renoprotective effects of eplerenone added to ACEi outweigh the renoprotective effects of the diuretic hydrochlorothiazide added to ACEi, in patients with diabetic nephropathy;

3. To investigate whether the benefits of eplerenone on top of ACEi are the result of the diuretic actions (potentiating the efficacy of ACEi) or secondary to the direct antifibrotic properties of eplerenone.

Patients visit the outpatient clinic at the 42th day of each study
period for assessment of the endpoints (blood pressure, proteinuria) and
safety parameters (potassium). At the 14th day of each period potassium
levels are checked, as well as dietary compliance (urinary sodium
excretion).

Combinations of:

1. Lisinopril 40 mg/d;

2. Hydrochlorothiazide 50 mg/d;

3. Eplerenone 25-50 mg/d;

4. Normal diet;

5. Sodium restricted diet.



Patients will be randomised into 4 groups, alike the DiNaMo study
(the ESCAPE study is an addendum to the DiNaMo study). The ESCAPE study
consists of 2 study periods of 6 weeks each, in which patients are
treated with lisinopril 40 mg once daily and eplerenone 25-50 mg once
daily. This is combined with a low sodium diet during 1 period, and a
normal diet during the other period. The antiproteinuric effect of these
regimens will be compared with the regimens of the DiNaMo study (which
contains placebo, and hydrochlorothiazide, on top of lisinopril 40 mg/d
and diet intervention).