How to know when little kidneys are in trouble: a review of current tools for diagnosing AKI in neonates.

Due to a plethora of risk factors, including prematurity, neonates are at risk for acute kidney injury (AKI) and, once established, AKI is associated with poor outcomes. The most widely used AKI biomarker is creatinine, despite research demonstrating creatinine to be a suboptimal tool for diagnosing neonatal AKI. This article uses an amalgamated case study to illustrate the inadequacies of creatinine for detection of preterm AKI and to present a range of novel AKI biomarkers relevant to the neonatal population. Clinical evaluation of novel AKI biomarkers is needed to improve precision and rapidity of AKI management in neonates.

Preclinical Evaluation of the Renal Toxicity of Oligonucleotide Therapeutics in Mice.

Antisense oligonucleotides (ASO) therapeutics hold great promise for the treatment of numerous diseases, and several ASO drugs have now reached market approval, confirming the potential of this approach. However, some candidates have also failed, due to limited biodistribution/uptake and poor safety profile. In pursuit of better delivery and higher cellular uptake, ASO are being optimized, and new chemistries are developed or conjugated with various ligands. While these developments may lead to candidates with higher potency, it is important to keep the safety aspects in sight and screen for potential toxicity in early phases of preclinical development to avoid subsequent failure in clinical development. Our understanding of ASO-mediated toxicity keeps improving with increased preclinical and clinical data available. In this chapter, we will focus on the assessment of renal toxicity in mice and describe methods to measure the levels of general urinary biomarkers as well as acute kidney injury biomarkers following ASO treatment.

Evaluation of cisplatin-induced injury in human kidney organoids.

Acute kidney injury (AKI) remains a major global healthcare problem, and there is a need to develop human-based models to study AKI in vitro. Toward this goal, we have characterized induced pluripotent stem cell-derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 µM cisplatin induces hepatitis A virus cellular receptor 1 (HAVCR1) and C-X-C motif chemokine ligand 8 (CXCL8) expression, DNA damage (γH2AX), and cell death in the organoids but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of proximal tubule-specific SLC22A2/organic cation transporter 2 (OCT2) for cisplatin. To improve viability, we developed a repeated low-dose regimen of 4 × 5 µM cisplatin over 7 days and found this caused less toxicity while still inducing a robust injury response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of cisplatin-induced injury, with the potential to identify new AKI biomarkers and develop better therapies.