Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI). The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44- and beta1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.

/pdf/mesenchymal-stem-cell-derived-microvesicles-protect-against-2mojoz3u00.pdf

Mesenchymal Stem Cell-Derived Microvesicles Protect Against Acute Tubular Injury

Preeclampsia is a clinical syndrome defined as the new onset of hypertension and proteinuria during the second half of pregnancy1 It afflicts 3% to 5% of pregnancies and is a leading cause of maternal mortality, especially in developing countries2,3 Because the only known remedy is delivery of the placenta, in developed countries preeclampsia is an important cause of premature delivery, usually medically indicated for the benefit of the mother This results in infant morbidity and substantial healthcare expenditure4 Despite the considerable morbidity and mortality, the cause of preeclampsia has remained enigmatic

Both hypertension and proteinuria implicate the endothelium as the target of the disease The hypertension of preeclampsia is characterized by peripheral vasoconstriction and decreased arterial compliance5,6 The proteinuria of preeclampsia is associated with a pathognomonic renal lesion known as glomerular endotheliosis, in which the endothelial cells of the glomerulus swell and endothelial fenestrations are lost7,8 Podocyturia has been recently associated with preeclampsia during clinical disease9; however, whether this is the cause or effect of proteinuria is unknown The glomerular filtration rate is decreased compared with normotensive pregnant women; in rare cases, acute renal failure may develop

Preeclampsia is a systemic vascular disorder that may also affect the liver and the brain in the mothers When the liver is involved, women may present with abdominal pain, nausea, vomiting, and elevated liver enzymes Pathological examination of the liver reveals periportal and sinusoidal fibrin deposition and, in more extreme cases, hemorrhage and necrosis10 The severe preeclampsia variant HELLP syndrome (hemolysis, elevated liver enzymes, low platelets) occurs in ≈20% of women with severe preeclampsia,11 and is named not only for the liver involvement, but also for the disorder of the coagulation system that develops12 Approximately 20% of …

Preeclampsia, a Disease of the Maternal Endothelium The Role of Antiangiogenic Factors and Implications for Later Cardiovascular Disease

Objective  To develop a practical evidence based list of clinical risk factors that can be assessed by a clinician at ≤16 weeks’ gestation to estimate a woman’s risk of pre-eclampsia. Design  Systematic review and meta-analysis of cohort studies. Data sources  PubMed and Embase databases, 2000-15. Eligibility criteria for selecting studies  Cohort studies with ≥1000 participants that evaluated the risk of pre-eclampsia in relation to a common and generally accepted clinical risk factor assessed at ≤16 weeks’ gestation. Data extraction  Two independent reviewers extracted data from included studies. A pooled event rate and pooled relative risk for pre-eclampsia were calculated for each of 14 risk factors. Results  There were 25 356 688 pregnancies among 92 studies. The pooled relative risk for each risk factor significantly exceeded 1.0, except for prior intrauterine growth restriction. Women with antiphospholipid antibody syndrome had the highest pooled rate of pre-eclampsia (17.3%, 95% confidence interval 6.8% to 31.4%). Those with prior pre-eclampsia had the greatest pooled relative risk (8.4, 7.1 to 9.9). Chronic hypertension ranked second, both in terms of its pooled rate (16.0%, 12.6% to 19.7%) and pooled relative risk (5.1, 4.0 to 6.5) of pre-eclampsia. Pregestational diabetes (pooled rate 11.0%, 8.4% to 13.8%; pooled relative risk 3.7, 3.1 to 4.3), prepregnancy body mass index (BMI) >30 (7.1%, 6.1% to 8.2%; 2.8, 2.6 to 3.1), and use of assisted reproductive technology (6.2%, 4.7% to 7.9%; 1.8, 1.6 to 2.1) were other prominent risk factors. Conclusions  There are several practical clinical risk factors that, either alone or in combination, might identify women in early pregnancy who are at “high risk” of pre-eclampsia. These data can inform the generation of a clinical prediction model for pre-eclampsia and the use of aspirin prophylaxis in pregnancy.

https://www.bmj.com/content/bmj/353/bmj.i1753.full.pdf

Clinical risk factors for pre-eclampsia determined in early pregnancy: systematic review and meta-analysis of large cohort studies

Preeclampsia is a systemic syndrome that occurs in 3 to 5% of pregnant women and classically manifests as new-onset hypertension and proteinuria after 20 weeks of gestation. Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. The only known cure is delivery of the placenta. Recent discoveries, however, have led to important advances in understanding the pathogenesis of the condition. Placental antiangiogenic factors are upregulated and disrupt the maternal endothelium. This change in the normal angiogenic balance toward an antiangiogenic state can result in hypertension, proteinuria, glomerular endotheliosis, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and cerebral edema—the clinical signs of preeclampsia and eclampsia. The regulation of these antiangiogenic factors in the placenta is unknown. The recent discoveries of upregulated antiangiogenic factors provide promise for future testing to predict and diagnose preeclampsia as well as therapeutic ta...

Pathogenesis of Preeclampsia

Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.

Pre-eclampsia: pathogenesis, novel diagnostics and therapies.

Urinary podocyte excretion as a marker for preeclampsia

The proteinuria of preeclampsia is associated with glomerular endotheliosis, and a role for damaged and lost podocytes (glomerular epithelial cells) in the development of proteinuria has received support from studies of patients with glomerular diseases. This study asked whether urinary excretion of viable podocytes, quantified by the expression of podocin and other podocyte-specific proteins, is observed in pregnant women with clinically confirmed preeclampsia. In addition, levels of angiogenic factors implicated in the pathogenesis of preeclampsia were estimated. They included soluble receptor for vascular endothelial growth factor, also called fms-like tyrosine kinase receptor-1 (sFlt-1); placental growth factor (PIGF); and serum soluble endoglin. The cross-sectional study recruited 33 pregnant women with preeclampsia, 11 with HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome, and 23 normotensive pregnant women. All of the 15 preeclamptic women evaluated and also those with HELLP syndrome, but not normotensive control subjects, had podocin-positive cells in their urine. Podocyturia was 100% sensitive and 100% specific for the diagnosis of preeclampsia, and the degree of proteinuria correlated positively with podocyturia. The positive predictive value of urinary podocyte excretion for the presence of preeclampsia was greater than that of sFlt-1, PIGF, or endoglin. Nevertheless, serum levels of sFlt-1 were significantly higher in women with preeclampsia or HELLP syndrome than in normotensive control women, and the same was the case for serum levels of soluble endoglin. Women with preeclampsia or HELLP syndrome had lower serum levels of free PlGF than did normotensive pregnant women. Urine levels of PlGF did not differ from those in normal women. Podocyturia is a very sensitive and specific marker for preeclampsia, and it may contribute to the development of proteinuria in affected women. Further studies may clarify the effects of dysregulated vascular endothelial growth factor on mechanisms regulating podocyte attachment.

David W. Rosenthal

Papers

Urinary podocyte excretion as a marker for preeclampsia

Urinary podocyte excretion as a marker for preeclampsia

Podocyturia is a sensitive and specific marker for preeclampsia