The incidence of end-stage kidney disease (ESKD) in the US ranks among the highest in the
world. ESKD is the last phase of chronic kidney disease when the kidneys are functioning
below 10-15% of normal capacity, and the patient is on dialysis. According to the US
Renal Data System (USRDS), 120,834 individuals started dialysis and nearly 524,000 people
were living on dialysis in 2017.1 Although advancement in technology and general medical
care has led to a modest decrease in mortality among dialysis patients, their mortality
rate remains extremely high at approximately 16.5 per 100 patient-years. The leading
cause of death among dialysis patients is cardiovascular disease (CVD), accounting for
almost 45% of deaths. Unfortunately, established therapies to prevent incident CVD in the
general population, such as renin-angiotensin system inhibitors or statins, have not been
shown to be effective in the dialysis population.
Sodium-glucose transporter type 2 (SGLT2) inhibitors are originally approved by FDA for
the treatment for type 2 diabetes. SGLT2 is localized to the brush border of the early
proximal tubule, and hence, SGLT2inhibitors induce osmotic diuresis and natriuresis but
do not activate the systemic renin-angiotensin-aldosterone system.2 Recent clinical
trials have consistently shown their potent renal and cardiovascular benefits in both
diabetic and non-diabetic patients, which cannot be explained only by their
glucose-lowering and diuretic properties. In fact, diuretics have not been shown to
reduce cardiovascular mortality and such benefits of SGLT2 inhibitors are clear even
among non-diabetic populations.3-5 Their renoprotective effect potentially extends to the
dialysis population where residual kidney function (RKF) still plays a major role in
solute clearance and volume control and has a strong association with patient outcomes.6
Patients who retain greater RKF can consume a more liberal diet and have better
nutritional status, less pill burden, better blood pressure, and less interdialytic fluid
gain with less frequent intradialytic hypotension, as well as greater quality of life and
better survival.6 The pathophysiology underlying the cardiovascular benefits of SGLT2
inhibitors are yet to be fully elucidated, but a recent in-vitro studies indicate its
direct effects on cardiomyocytes. Therefore, the investigators hypothesize that dialysis
patients also benefit from SGLT2 inhibitors even if they do not have any RKF.
Efficacy and safety studies with SGLT2 inhibitors did not enroll end-stage kidney disease
(ESKD) patients on dialysis. Empagliflozin, canagliflozin, and dapagliflozin can be
started if the glomerular filtration rate is more than 20-25 mL/min per 1.73 m2 and can
be continued until dialysis initiation or kidney transplant. From a pharmacokinetics
standpoint, those SGLT2 inhibitors are extensively metabolized by glucuronidation into
inactive metabolites, and are not likely to cause dose-dependent toxicity even in ESKD.
Nevertheless, extra caution is necessary for their use in the setting of ESKD because
SGLT2 inhibitors are not well dialyzable due to large distribution volumes and high
protein binding rates.
Our overall goal is to conduct a non-randomized feasibility clinical trial of
empagliflozin in the dialysis population to obtain data that will help plan future
larger, sufficiently powered efficacy clinical trials. The investigators plan to enroll a
total of 24 dialysis patients (18 patients on hemodialysis and 6 patients on peritoneal
dialysis). After one month of the run-in period, participants will take oral
empagliflozin for 3 months.
*Hemodialysis is a form of renal replacement therapy that utilizes an external filter
(dialyzer) to remove wastes from the bloodstream. Peritoneal dialysis utilizes the
peritoneum as a filter to remove wastes.