Immunologic aspects of preeclampsia.

Preeclampsia is a syndrome with multiple etiologies. The diagnosis can be made without proteinuria in the presence of dysfunction of at least 1 organ associated with hypertension. The common pathophysiological pathway includes endothelial cell activation, intravascular inflammation, and syncytiotrophoblast stress. There is evidence to support, among others, immunologic causes of preeclampsia. Unlike defense immunology, reproductive immunology is not based on immunologic recognition systems of self/non-self and missing-self but on immunotolerance and maternal-fetal cellular interactions. The main mechanisms of immune escape from fetal to maternal immunity at the maternal-fetal interface are a reduction in the expression of major histocompatibility complex molecules by trophoblast cells, the presence of complement regulators, increased production of indoleamine 2,3-dioxygenase, activation of regulatory T cells, and an increase in immune checkpoints. These immune protections are more similar to the immune responses observed in tumor biology than in allograft biology. The role of immune and nonimmune decidual cells is critical for the regulation of trophoblast invasion and vascular remodeling of the uterine spiral arteries. Regulatory T cells have been found to play an important role in suppressing the effectiveness of other T cells and contributing to local immunotolerance. Decidual natural killer cells have a cytokine profile that is favored by the presence of HLA-G and HLA-E and contributes to vascular remodeling. Studies on the evolution of mammals show that HLA-E, HLA-G, and HLA-C1/C2, which are expressed by trophoblasts and their cognate receptors on decidual natural killer cells, are necessary for the development of a hemochorial placenta with vascular remodeling. The activation or inhibition of decidual natural killer cells depends on the different possible combinations between killer cell immunoglobulin-like receptors, expressed by uterine natural killer cells, and the HLA-C1/C2 antigens, expressed by trophoblasts. Polarization of decidual macrophages in phenotype 2 and decidualization of stromal cells are also essential for high-quality vascular remodeling. Knowledge of the various immunologic mechanisms required for adequate vascular remodeling and their dysfunction in case of preeclampsia opens new avenues of research to identify novel biological markers or therapeutic targets to predict or prevent the onset of preeclampsia.

Long-term impact of COVID-19 among maintenance haemodialysis patients.

BACKGROUND: Maintenance haemodialysis (MHD) patients have a high risk of initial mortality from coronavirus disease 2019 (COVID-19). However, long-term consequences of this disease in the MHD population are poorly described. We report the clinical presentation, outcome and long-term follow-up of MHD patients affected by COVID-19 in a multicentric cohort from the Paris, France area. METHODS: We conducted a retrospective analysis of clinical presentation and long-term follow-up of MHD patients affected by COVID-19 in 19 MHD centres in the Paris, France area. RESULTS: In this cohort of 248 patients with an initial mortality rate of 18%, age, comorbidities, dyspnoea and previous immunosuppressive treatment were associated with death at <30 days. Among the 203 surviving patients following the acute phase, long-term follow-up (median 180 days) was available for 189 (93%) patients. Major adverse events occurred in 30 (16%) patients during follow-up, including 12 deaths (6%) after a median of 78 days from onset of symptoms. Overall, cardiovascular events, infections and gastrointestinal bleeding were the main major adverse events. Post-COVID-19 cachexia was observed in 25/189 (13%) patients. Lower initial albuminaemia was significantly associated with this cachexia. No reinfection with severe acute respiratory syndrome coronavirus 2 was observed. CONCLUSIONS: This work demonstrates the long-term consequences of COVID-19 in MHD patients, highlighting both initial and long-term severity of the disease, including severe cachexia.

SARS-CoV-2 Antibodies in Hemodialysis Patients Six Months after Infection Compared to Healthcare Workers.

BACKGROUND: The humoral response to SARS-CoV-2 infection in hemodialysis patients needs to be clarified. METHODS: In this retrospective study performed in two dialysis facilities, we measured the circulating levels of SARS-CoV-2 antibodies in patients who were on maintenance hemodialysis during the first wave of the epidemic in March and April 2020 and were still alive 6 months later. We also investigated associations between the patients diagnosed as infected during the first wave and several clinical, biological, and radiological parameters of COVID-19. Finally, we compared these circulating levels of SARS-CoV-2 antibodies with those of a control group of healthcare workers infected during the same period. RESULTS: Of the 299 hemodialysis patients who recovered from the first wave of the epidemic 6 months before, 59 had a positive SARS-CoV-2 antibody whereas only 45 patients were diagnosed as infected during the first wave of the epidemic. All infected hemodialysis patients developed circulating antibodies. Using a clustering method, a significant correlation was identified between the cluster with the lowest circulating levels of SARS-CoV-2 antibodies and the severity of COVID-19 based on several parameters including CRP, BNP, lymphocyte count, neutrophil-lymphocyte ratio, and oxygen requirements, as well as pulmonary involvement on chest scan. Moreover, the circulating levels of the SARS-CoV-2 antibodies in surviving hemodialysis patients (n = 59) were similar to those of the control group (n = 17). CONCLUSION: The main finding of this study is that all of the surviving hemodialysis patients who were diagnosed with SARS-CoV-2 infection from March to April 2020 developed a persistent humoral response with significant circulating levels of SARS-CoV-2 antibodies, 6 months later. Another important finding is that surviving hemodialysis patients who had more severe disease had lower circulating levels of SARS-CoV-2 antibodies. Finally, circulating levels of SARS-CoV-2 antibodies were similar in surviving hemodialysis patients and healthcare workers without kidney disease.

[Potential value of placental angiogenic factors as biomarkers in preeclampsia for clinical physicians]. / Intérêts potentiels des facteurs angiogéniques placentaires comme biomarqueurs dans la pré-éclampsie pour le clinicien.

The role of angiogenic factors in the onset of clinical manifestations of preeclampsia was demonstrated in 2003 by the implication of sFlt-1, PlGF and VEGF, and in 2006 by the implication of soluble endoglin. Placental ischemia and inflammation observed in preeclampsia alter both the production and progression of angiogenic factors during pregnancy. During the first trimester, the combination of PlGF with clinical, biophysical and biological factors results in a better test than the conventional one. However, the clinical value of this method remains to be confirmed. During the second and third trimesters, the sFlt-1/PlGF ratio may be used, with or without pre-existing renal disease, for short-term prediction, diagnosis, and prognosis, and to evaluate the effectiveness of preeclampsia treatment. While a sFlt-1/PlGF ratio<38 and≤33, respectively, rules out the short-term onset and diagnosis of preeclampsia, a sFlt-1/PlGF ratio≥85 between 20 and 34 weeks of pregnancy and≥110 beyond 34 weeks of pregnancy confirms a diagnosis of preeclampsia. Angiogenic and non-angiogenic preeclampsia are identified by a sFlt-1PlGF≥85 and<85, respectively, with the risk of maternal and fetal complications at two weeks differing between the two. Similarly, a sFlt-1/PlGF ratio>665 and>205, respectively, is a good short-term predictor of adverse outcomes of early and late-onset preeclampsia. These values could be incorporated into future guidelines for better clinical management of preeclampsia.

How should women with pre-eclampsia be followed up? New insights from mechanistic studies.

Understanding of the maternal syndrome of pre-eclampsia has greatly improved over the past 5 years. Specifically, the notion has emerged that the placenta is a source of antiangiogenic factors, such as soluble fms-like tyrosine kinase 1, that can progressively impair the mother's vascular and glomerular function throughout pregnancy. This impairment can be harmless during normal pregnancy, but in cases of defective placentation, concentrations of antiangiogenic factors increase to a level that compromises vital vascular functions in the short term and jeopardizes long-term maternal and fetal outcomes. In both pre-eclamptic and healthy pregnancies, the transient imbalance between angiogenic and antiangiogenic factors elicited by pregnancy acts as a 'stress test' for the endothelium, particularly in the glomerular capillary bed. Women who do not pass this test (i.e. those who develop pre-eclampsia or gestational hypertension) should be screened for glomerular disease, and their cardiovascular risk should be carefully monitored throughout life.

[New insights in the pathophysiology of preeclampsia and potential therapeutic implications]. / Avancées récentes dans la compréhension de la physiopathologie de la prééclampsie et conséquences thérapeutiques potentielles.

Preeclampsia still represents the leading cause of feto-maternal morbi-mortality in developed countries. The reason for the persistence of such gravity results to a large extent from the lack of clear knowledge concerning the pathophysiology of this disease and consequently the lack of adequate therapy apart from placental extraction. Preeclampsia is the clinical result of a generalized maternal systemic endothelial dysfunction secondary to an abnormal placental development. The close mechanisms of the abnormal placental development remain elusive. Currently, only epidemiologic risk factors and some immuno-genetic dysfunctions have been identified to favour abnormal placentation and preeclampsia. On the other hand, the identification of two circulating anti-angiogenic proteins, the soluble-fms-like tyrosine kinase-1 and the soluble endoglin, produced in excess by the placenta during the preeclampsia, allow us now to connect clearly abnormal placentation to an endothelial dysfunction. The excessive production of these two anti-angiogenic proteins induces an endothelial dysfunction by inhibiting circulating proangiogenic factors such as the placental growth factor, the vascular endothelial growth factor but also the transforming growth factor-beta. So far, numerous placental factors have been proposed, however none has been able to induce a real typical phenotype of preeclampsia. This discovery has two potential medical impacts. Firstly, the potential possibility, in the future, to measure these surrogate markers in the blood or urine to predict the onset of preeclampsia before its clinical manifestations. Secondly the theoretical possibility to reverse the angiogenic imbalance state of preeclamspsia and consequently to correct the maternal syndrome transiently by adding exogenous proangiogenic factor.

Evaluation of post-puncture bleeding time of arteriovenous fistulas with IRIS® bandage.

PURPOSE: Our aim was to evaluate the safety and effectiveness of the IRIS® bandage (Nephrokit®) on post-puncture bleeding compared to conventional manual compression. METHODS: Sixty-four patients, hemodialyzed with an arteriovenous fistula, were enrolled in a 3-week prospective study. Conventional manual compression was used during the first week, the IRIS® bandage during the second week and conventional manual compression again during the third week. The outcomes analyzed were the persistence or absence of bleeding 3 minutes post-puncture with IRIS® device compared to conventional manual compression. The safety of the IRIS® bandage was also evaluated. RESULTS: Rates of persistent bleeding 3 minutes post-puncture at arterial sites were 53±6% and 56±5%, respectively, during the first and third weeks (conventional compression) versus 18±5% during the second week (IRIS® bandage). Similarly, rates of persistent bleeding 3 minutes post-puncture at venous sites were 45±6% and 45±6%, respectively, with conventional compression versus 23±5% with the IRIS® bandage. The difference between the IRIS® device and conventional compression therefore proved highly statistically significant (p<0.05) for both arterial and venous puncture sites. No particular adverse events were observed with the IRIS® device. CONCLUSIONS: Post-puncture bleeding time at arteriovenous fistula sites is significantly shortened by the IRIS® bandage in comparison with conventional manual compression.

[Cinacalcet impact on calcium homeostasis and bone remodeling in 13 renal transplanted patients with hyperparathyroidism and hypercalcaemia]. / Effet du cinacalcet sur l'homéostasie calcique et le remodelage osseux chez 13 transplantés rénaux présentant une hyperparathyroïdie avec hypercalcémie.

The purpose of the study is to assess the impact of cinacalcet on calcium and bone remodeling, in post-renal transplanted patients with persistent hypercalcaemia secondary to hyperparathyroidism. Thirteen renal-transplanted adult recipients with a glomerular filtration rate over 30 ml/min/1.73 m(2), a total serum calcium>2.60 mmol/l with ionized calcium>1.31 mmol/l and a parathyroid hormone serum level over 70 pg/ml, were treated with cinacalcet for 4 months followed by a 15-day wash out. The results show that cinacalcet lowers significantly total and ionized calcium respectively from 2,73 (2,67-2,86) to 2,31 (2,26-2,37) mmol/l (P<0.05) and from 1,39 (1,37-1,47) to 1,21 (1,15-1,22) mmol/l (P<0.05) with no alteration of the 24-hour urine calcium/creatinine ratio and no significant expected PTH serum level suppression (153 [115-214,9] and 166 [122-174] pg/ml). On the other hand, fasting urine calcium was significantly decreased from 0,61 (0,27-1,02) to 0,22 (0,15-0,37) (P<0.05) and bone-specific alkaline phosphatases increased from 20,5 (13-46,6) to 33,8 (12-58,9) ng/ml, upon cinacalcet treatment. After its discontinuation, all these effects were reversible. In conclusion, cinacalcet normalizes total and ionized calcium in renal-transplanted recipients with hypercalcemia secondary to hyperparathyroidism through a mechanism that could be independent of PTH serum level suppression. The increase in bone-specific alkaline phosphatases, biochemical markers of bone accretion and the significant decrease in fasting urine calcium suggest the possibility of a beneficial impact of cinacalcet on bone remodeling.

[Plasma creatinine, Cockcroft and MDRD: validity and limitations for evaluation of renal function in chronic kidney disease]. / Mesure et estimation du débit de filtration glomérulaire : quels outils pour la prise en charge de la maladie rénale chronique ?

The glomerular filtration rate (GFR) is the best indicator of renal function. Measurement of the plasma creatinine level is the simplest laboratory test for estimating GFR. The plasma creatinine assay is currently being standardized, which will improve its reproducibility. It remains the best indicator for the diagnosis and follow-up of acute renal failure. Conversely, diagnosis and follow-up of chronic kidney disease are based on the GFR value, which is routinely estimated from formulas derived from plasma creatinine levels. The formula developed from the MDRD study performs better than the Cockcroft formula for nearly all patients and clinical situations and should replace it. GFR should be measured directly, by the urinary clearance of exogenous markers, in any situation in which the precision of the formula used is insufficient for medical decision-making. This requires defining for any given patient and situation both the desired precision and that expected from the formulas.