Megalin-targeting and ROS-responsive elamipretide-conjugated polymeric prodrug for treatment of acute kidney injury.

Acute kidney injury (AKI) is associated with both kidney function loss and increased mortality. In the pathological progression of ischemia-reperfusion-induced AKI, the surge of reactive oxygen species (ROS) plays a crucial role. To combat this, mitochondrial-targeted antioxidant therapy shows great promise as mitochondria are the primary source of ROS in AKI. However, most strategies aiming to target mitochondria directly result in nanodrugs that are too large to pass through the glomerular system and reach the renal tubules, which are the main site of damage in AKI. This study focused on synthesizing a Megalin receptor-targeted polymeric prodrug, low molecular weight chitosan-thioketal-elamipretide (LMWC/TK/Ela), to mitigate excessive ROS in renal tubular epithelial cells for AKI. This soluble polymeric prodrug has the ability to successfully reach the tubular site by crossing the glomerular barrier. Once there, it can responsively release elamipretide, which possesses excellent antioxidative properties. Therefore, this research offers a novel approach to actively target renal tubular epithelial cells and intracellular mitochondria for the relief of AKI.

Megalin-targeted acetylcysteine polymeric prodrug ameliorates ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI), a condition associated with reactive oxygen species (ROS), causes high mortality in clinics annually. Active targeted antioxidative therapy is emerging as a novel strategy for AKI treatment. In this study, we developed a polymeric prodrug that targets the highly expressed Megalin receptor on proximal tubule cells, enabling direct delivery of N-Acetylcysteine (NAC) for the treatment of ischemia reperfusion injury (IRI)-induced AKI. We conjugated NAC with low molecular weight chitosan (LMWC), a biocompatible and biodegradable polymer consisting of glucosamine and N-acetylglucosamine, to enhance its internalization by tubular epithelial cells. Moreover, we further conjugated triphenylphosphonium (TPP), a lipophilic cation with a delocalized positive charge, to low molecular weight chitosan-NAC in order to enhance the distribution of NAC in mitochondria. Our study confirmed that triphenylphosphonium-low molecular weight chitosan-NAC (TLN) exhibits remarkable therapeutic effects on IRI-AKI mice. This was evidenced by improvements in renal function, reduction in oxidative stress, mitigation of pathological progress, and decreased levels of kidney injury molecule-1. These findings suggested that the polymeric prodrug TLN holds promising potential for IRI-AKI treatment.

Long-term effects of immunosuppression treatment on IgA nephropathy: a systematic review and meta-analysis.

BACKGROUND: Immunoglobulin A (IgA) nephropathy is an immune complex-mediated glomerulonephritis; however, the role of immunosuppression is still controversial, and there is a lack of studies on the long-term efficacy of immunosuppressive drugs in the treatment of the disease. We conducted a meta-analysis to examine the long-term effects of immunosuppressive drugs. METHODS: To identify random control trial articles on immunosuppressive drugs in the treatment of IgA nephropathy with a follow-up time >3 years, the following databases were searched: MEDLINE (1946 to August 2021), EMBASE (2000 to August 2021), PubMed (2000 to August 2021), and Cochrane library (2000 to August 2021). After screening, the Cochrane Handbook of Systematic Reviews of Interventions was used to examine the bias of the studies, Stata16.0 software was used for the analysis, and forest plots were used to present the results. RESULTS: A total of 744 patients from 7 studies were included in the study. The results of the meta-analysis showed that the long-term renal function integrity rate in the experimental group treated with immunosuppressive drugs was higher than that in the control group treated with placebos [risk ratio (RR) =1.10, 95% confidence interval (CI): 1.00, 1.22, Z=1.978, P=0.048], the efficacy of immunosuppressive drugs during the 3-6-year follow-up period (RR =1.07, 95% CI: 0.92, 1.23, Z=0.864, P=0.388) was similar to that of immunosuppressive drugs during the 8-10-year follow-up period (RR =1.14, 95% CI: 1.00, 1.30, Z=1.909, P=0.056), the efficacy of immunosuppressive drug therapy alone (RR =1.11, 95% CI: 1.00, 1.24, Z=1.914, P=0.056) was similar to that of immunosuppressive combination drug therapy (RR =1.07, 95% CI: 0.84, 1.35, Z=0.549, P=0.583), and the adverse reactions in the immunosuppressive drug group were higher than those in the placebo group (RR =1.59, 95% CI: 1.38, 1.85, Z=6.230, P=0.000). DISCUSSION: The use of immunosuppressive drugs can improve the long-term effects of IgA nephropathy treatment, but consideration should be given to the increase of adverse reactions during treatment.