Safety and Tolerability Study of an Intravenously Administered Small Interfering Ribonucleic Acid (siRNA) Post On-Pump Cardiothoracic Surgery in Patients at Risk of Acute Kidney Injury

@article{Demirjian2017SafetyAT,
  title={Safety and Tolerability Study of an Intravenously Administered Small Interfering Ribonucleic Acid (siRNA) Post On-Pump Cardiothoracic Surgery in Patients at Risk of Acute Kidney Injury},
  author={Segav Demirjian and Gorav Ailawadi and Martin A. Polinsky and Daniel Bitr{\'a}n and Shuli Silberman and Stanton Keith Shernan and Michel Burnier and Marta Hamilton and Elizabeth C. Squiers and Shai Erlich and Daniel Rothenstein and Samina Y. Khan and Lakhmir S. Chawla},
  journal={Kidney International Reports},
  year={2017},
  volume={2},
  pages={836 - 843}
}

Figures and Tables from this paper

Teprasiran, a Small Interfering RNA, for the Prevention of Acute Kidney Injury in High-Risk Patients Undergoing Cardiac Surgery

The incidence, severity, and duration of early AKI in high-risk patients undergoing cardiac surgery were significantly reduced after teprasiran administration.

Therapeutic siRNA: State-of-the-Art and Future Perspectives

Details on the mode of action and clinical status of the various siRNA therapeutics are provided, before giving an outlook on issues regarding the future of siRNA drugs and on their potential as one emerging standard modality in pharmacotherapy.

Drugs in Development for Acute Kidney Injury

A revolution in the scientific understanding of the pathogenesis of AKI has led to the identification of potential therapeutic targets, which include pathways involved in inflammation, cellular repair and fibrosis, cellular metabolism and mitochondrial function, oxidative stress, apoptosis, and hemodynamics and oxygen delivery.

Incidence, risk factors and prognosis of acute kidney injury in patients treated with immune checkpoint inhibitors: a retrospective study

Multivariate Cox regression analysis showed that anemia, Alb < 30 g/L, AKI occurrence, and diuretic use were independent risk factors for death in patients treated with ICIs, while high baseline BMI, other tumor types, ACEI/ARB use, and chemotherapy use were protective factors for patient death.

Kidney-Targeted Cytosolic Delivery of siRNA Using a Small-Sized Mirror DNA Tetrahedron for Enhanced Potency

The kidney preference and the tubular cell uptake property of the mirror DNA nanostructure could be successfully harnessed for kidney-targeted intracellular delivery of p53 siRNA to treat acute kidney injury (AKI) in mice.

Plasmacytoma Variant Translocation 1 (PVT1) Gene as a Potential Novel Target for the Treatment of Diabetic Nephropathy

The application of RNAi-based therapy to delay DN progression in a murine DN model showed that silencing of PVT1 reduced kidney hypertrophy, proteinuria, serum creatinine, serum TGF-β1, serum insulin decline, glomerular and mesangial areas, and increased Creatinine clearance in diabetic mice to levels closer to the age-matched controls.

References

SHOWING 1-10 OF 28 REFERENCES

Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomized, single-blind, placebo-controlled, phase 1 trial

A novel strategy involving small interfering RNA (siRNA) to block translation of PCSK9 mRNA is described, providing proof of concept of a novel way to target enzymes of therapeutic interest and safety and tolerability.

siRNA targeted to p53 attenuates ischemic and cisplatin-induced acute kidney injury.

Data indicate that rapid delivery of siRNA to proximal tubule cells follows intravenous administration, suggesting potential therapeutic benefit for ischemic and nephrotoxic kidney injury.

p53 target Siva regulates apoptosis in ischemic kidneys.

It is reported here that the p53 proapoptotic target Siva and its receptor CD27, a member of the tumor necrosis factor receptor family, are upregulated following renal ischemia-reperfusion injury (IRI) and inhibition of Siva using antisense oligonucleotides conferred functional and morphological protection and prevented apoptosis postrenal IRI in mice.

Activation and involvement of p53 in cisplatin-induced nephrotoxicity.

The involvement of p53 in cisplatin-induced renal cell apoptosis and nephrotoxicity is suggested, which limits its use and efficacy in cancer treatment.

p53 is renoprotective after ischemic kidney injury by reducing inflammation.

In contrast to the rat, inflammation characterizes ischemic AKI in mice; leukocyte p53 is protective by reducing the extent and duration of this inflammation and by promoting the anti-inflammatory M2 macrophage phenotype.

P53 mediates the apoptotic response to GTP depletion after renal ischemia-reperfusion: protective role of a p53 inhibitor.

It is concluded that p53 is an important mediator of apoptosis during states of GTP depletion and inhibitors of p53 should be considered in the treatment of ischemic renal injury.

Acute kidney injury, mortality, length of stay, and costs in hospitalized patients.

Modest changes in SCr were significantly associated with mortality, LOS, and costs, even after adjustment for age, gender, admission International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis, severity of illness (diagnosis-related group weight), and chronic kidney disease.

MDM2 (murine double minute-2) links inflammation and tubular cell healing during acute kidney injury in mice.

In vitro experiments confirmed that MDM2 is required to induce mRNA expression and secretion of NFκB-dependent cytokines upon Toll-like receptor stimulation by enhanced binding ofNFκB to cytokine promoter-binding sites, and links inflammation and epithelial healing during AKI.

Acute Kidney Injury Is Associated With Increased Long-Term Mortality After Cardiothoracic Surgery

The risk of death associated with AKI after cardiothoracic surgery remains high for 10 years regardless of other risk factors, even for those patients with complete renal recovery, so improved renal protection and closer postdischarge follow-up of renal function may be warranted.