Low-dose aspirin in pregnancy: who? when? how much? and why?

PURPOSE OF REVIEW: The use of low dose aspirin (LDA) has become routine in prenatal care for a variety of diagnoses, most importantly in women with a history of preeclampsia and associated poor pregnancy outcomes. Although LDA is currently indicated in patients considered to be at risk for development of preeclampsia, optimal dosing, timing of treatment initiation, and persons of benefit are under investigation. Several studies have also looked at LDA treatment and its effect on other maternal and fetal outcomes. This review summarizes the current guidelines for the use of LDA, incorporating the most recent research findings, and offers possible future implications of LDA treatment. RECENT FINDINGS: Over 10 years ago, the American College of Obstetricians and Gynecologists, the World Health Organization, and the United States Preventive Service Task Force began publishing guidelines focused on the use of LDA in pregnancy. Since the release of these guidelines, several large studies have re-evaluated the use of LDA with a focus on initiation of treatment and dosing. The combined results of these studies suggest a decreased rate of preeclampsia at aspirin doses >100 mg when treatment is initiated prior to 16 weeks of gestation. SUMMARY: Overall, early initiation of LDA has been shown to decrease the development of preeclampsia in patients considered at increased risk. Current literature suggests increasing the recommended dose to >100 mg to optimize these risk reductions. Although LDA use seems promising for other outcomes like preterm delivery and intrauterine growth restriction, further studies to strengthen recommendations are warranted.

Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death.

Sphingolipids are a family of lipids that regulate the cell cycle, differentiation and cell death. Sphingolipids are known to play a role in the induction of apoptosis, but a role for these lipids in necroptosis is largely unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, does not require ATP. Necroptosis can be induced under a variety of conditions, including nutrient deprivation and plays a major role in ischaemia/reperfusion injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in several organs. Thus, we hypothesized that sphingolipids mediate nutrient-deprivation-induced necroptosis. To address this, we utilized mouse embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 kinase-dependent and caspase-independent. Ceramides, sphingosine (Sph) and sphingosine 1-phosphate (S1P) were increased following 2DG/AA treatment. Cells lacking neutral ceramidase (nCDase(-/-)) were protected from 2DG/AA. Although nCDase(-/-) cells generated ceramides following 2DG/AA treatment, they did not generate Sph or S1P. This protection was stimulus-independent as nCDase(-/-) cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin (TN) or thapsigargin (TG)]. nCDase(-/-) MEFs had higher autophagic flux and mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to necroptosis. These data indicate that loss of nCDase protects cells from nutrient- deprivation-induced necroptosis via autophagy, and clearance of damaged mitochondria. Results suggest that nCDase is a mediator of necroptosis and might be a novel therapeutic target for protection from ischaemic injury.

Renal glycosphingolipid metabolism is dysfunctional in lupus nephritis.

Nearly one half of patients with lupus develop glomerulonephritis (GN), which often leads to renal failure. Although nephritis is diagnosed by the presence of proteinuria, the pathology of nephritis can fall into one of five classes defined by different forms of tissue injury, and the mechanisms involved in pathogenesis are not completely understood. Glycosphingolipids are abundant in the kidney, have roles in many cellular functions, and were shown to be involved in other renal diseases. Here, we show dysfunctional glycosphingolipid metabolism in patients with lupus nephritis and MRL/lpr lupus mice. Specifically, we found that glucosylceramide (GlcCer) and lactosylceramide (LacCer) levels are significantly higher in the kidneys of nephritic MRL/lpr lupus mice than the kidneys of non-nephritic lupus mice or healthy controls. This elevation may be, in part, caused by altered transcriptional regulation and/or activity of LacCer synthase (GalT5) and neuraminidase 1, enzymes that mediate glycosphingolipid metabolism. We show increased neuraminidase 1 activity early during the progression of nephritis (before significant elevation of GlcCer and LacCer in the kidney). Elevated levels of urinary LacCer were detected before proteinuria in lupus mice. Notably, LacCer levels were higher in the urine and kidneys of patients with lupus and nephritis than patients with lupus without nephritis or healthy controls. Together, these results show early and significant dysfunction of the glycosphingolipid metabolic pathway in the kidneys of lupus mice and patients with lupus nephritis and suggest that molecules in this pathway may serve as early markers in lupus nephritis.

Glycosphingolipids and kidney disease.

Glycosphingolipids, derived from the addition of sugar-moieties to the sphingolipid ceramide, are highly abundant in the kidney. Glycosphingolipids are known to play an important role in organ function at least in part from inherited lipid storage diseases such as Anderson-Fabry disease (Fabry's disease; FD) that results from a mutation in alpha-galactosidase a (α-GLA or α-Gal A), the enzyme responsible for catalyzing the removal of terminal galactose residues from glycosphingolipids. The inactivation in α-GLA in FD results in the accumulation of glycosphingolipids, including globosides and lactosylceramides, which manifests as several common pathologies including end-stage kidney disease. More recently, glycosphingolipids and other sphingolipids have become increasingly recognized for their roles in a variety of other kidney diseases including polycystic kidney disease, acute kidney injury, glomerulonephritis, diabetic nephropathy and kidney cancer. This chapter reviews evidence supporting a mechanistic role for glycosphingolipids in kidney disease and discusses data implicating a role for these lipids in kidney disease resulting from metabolic syndrome. Importantly, inhibitors of glycosphingolipid synthesis are well tolerated in animal models as well as in humans. Thus, an increased understanding of the mechanisms by which altered renal glycosphingolipid metabolism leads to kidney disease has great therapeutic potential.