Recent studies have estimated that chronic kidney diseases (CKDs) affect around 850
million people worldwide (one in ten adults). The global burden of CKD is increasing and
is projected to become the fifth most common cause of years of life lost globally by 2040 [1].
Since CKD is mostly irreversible and progressive, patients who advance to end-stage renal
disease (ESRD) require dialysis or renal transplantation, which negatively affect quality of
life and have a large impact on healthcare systems. It has been estimated that the costs of
dialysis and transplantation consume 2–4% of annual healthcare budgets in high-income
countries [1,2]. Moreover, kidney transplantation is associated with a high risk of morbidity
and mortality, after rejection, infections, and cancer development, as a consequence of the
continuous immunosuppression required [3]. Therefore, kidney disease has a major effect
on global health and deserves greater attention for the development and improvement of
new detection methods and treatments.
Oligonucleotide (ON) therapeutics, such as those based on antisense oligonucleotides
(ASOs), small interfering RNA (siRNA), microRNA (miRNA), aptamers, and decoys, are
promising agents that have gained importance during the last decades. As of January 2020,
ten oligonucleotide drugs have received regulatory approval from the United States Food
and Drug Administration (FDA) and dozens are under clinical trials [4,5]. However, a
major obstacle that still hampers the development of new oligonucleotide-based therapies is the difficulty in directing them to specific organs. The kidneys are highly vascularized
organs that receive up to 25% of cardiac output, and are susceptible to targeting
by most systemic administration routes. Additionally, the glomerular filtration barrier
has evolved to filter molecules smaller than 50 kDa in size, which includes the majority
of oligonucleotides commonly used in therapeutics, allowing their access to the tubular
epithelium. However, this route mostly favors targeting of the liver and other peripheral
organs, such as the spleen, due to its vascularized anatomy and scavenging functions.
Indeed, at least half of the approved oligonucleotide-based drugs have been developed for
liver therapy [4,5]. The unresolved problem of non-specific and off-target effects is a second
major obstacle yet to be overcome by improving delivery methods. Importantly, toxicity,
and side-effects of oligonucleotides have already been described, including inhibition of
unspecific genes, oversaturation of the endogenous small RNA processing pathways, or
non-complementary binding of the oligonucleotide to unintended RNAs with a sequence
similar to the target RNA [6–10]. In this review, we will outline the different oligotherapeutic
strategies developed to date for the treatment of renal diseases, with a specific focus on
the delivery methods and nanotechnological platforms developed, and their potential to
achieve efficient kidney delivery.

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This entry is adapted from the peer-reviewed paper 10.3390/biomedicines9030303