Individuals with
chronic kidney disease (CKD) are at a disproportionately high risk of
cardiovascular events. Mechanistically, high salt and water retention cause
sympathetic nervous system over reactivity combined with the activation of the
renin-angiotensin-aldosterone system (RAAS). Downstream pathophysiological pathways
include inflammation, oxidative stress, platelet activation and reduced hormone
production, all which combine to promote adverse cardiovascular complications.
The 14th of March marks World Kidney Day. The main theme this year
centres on broader access to therapy and care. Mitigating the adverse
cardiovascular manifestations are a key focus for modern therapeutics and the
need to clearly identify patients at greater risk using predictive biomarkers
remain crucial in managing disease.
Anaemia is a
very common complication in CKD and is linked with a decrease in endogenous Erythropoietin
(EPO), iron deficiency and inflammation. Anaemia in CKD patients is associated
with worse survival and increases in morbidity and mortality. EPO is a hormone
produced in the kidneys mainly responsible for red blood cell protection and
production. Autoantibodies against the EPO receptor (EPOR) have been detected
in patients with CKD. Autoantibodies are “self-reactive” antibodies often
linked to autoimmune and inflammatory diseases.
Recently, post
hoc analysis of the CREDANCE trial assessed the association of EPOR
autoantibodies with both kidney and cardiovascular complications and mortality.
The authors found higher anti-EPOR autoantibodies were significantly associated
with cardiovascular death and all cause mortality. Whilst this observational
finding requires further investigation with other studies, this provides early
evidence of how anti-EPOR autoantibodies may be valuable predictive biomarkers
of cardiovascular risk in CKD patients. Whilst useful for stratifying patients,
the primary focus remains effective therapies which can help these patients at
high risk.
Recently, a
class of diabetic therapeutics, the sodium glucose transporter-2 (SGLT2)
inhibitors, have shown utility in CKD. SGLT2 inhibitors reduce CKD progression,
cardiovascular events and extend patient survival. Their primary mechanism
involves decreasing glucose reabsorption in kidney tubules by lowering SGLT2
expression. It is hypothesized that these compounds increase haemoglobin, haematocrit
and EPO synthesis. Canagliflozin, a SGLT2 inhibitor was used to treat patients
in the CREDANCE trial. Analysis concluded that treatment was beneficial in
attenuating anaemia in all patients with or without anti-EPOR autoantibodies.
While no doubt
extremely useful, there remains some caution in the broad prescription of SGLT2
inhibitors. There are concerns of increased risk of urinary tract infections,
foot, leg and toe amputations in patients. SGLT2 inhibitors are also expensive
and is therefore crucial to identify subgroups of patients who would draw the
maximum benefit from treatment.
About Synexa and Scientific Strategies
Synexa is a specialized biomarker and bioanalytical services firm,
established over 20 years ago. We have been supporting our clients at all
stages of clinical development, from discovery to phase 3 studies. Our services
cover analysis across the biological continuum, from nucleic acid, soluble
biomarker, cell and tissue. Our team of dedicated scientists, working across
labs in South Africa, Europe, the UK and US, relish solving intricate and
challenging biological problems.
A key extension of this is Synexa’s Scientific Strategies Team. There
are many challenges and risks progressing a compound into clinical
development. Synexa’s Scientific
Strategies team can help de-risk your development by providing support around
key biomarker and bioanalytical considerations. The dedicated team can offer
standalone consulting support, providing objective, actionable solutions to
your biomarker and bioanalytical challenges.
References
·
Koshino et al.
2024. Kidney Int Rep. 9(347-355)
·
Portolés et al. 2021. Front. Med. 8:642296
