Oxidative Stress, Lipid Peroxidation and Ferroptosis Are Major Pathophysiological Signatures in the Placental Tissue of Women with Late-Onset Preeclampsia.

Preeclampsia, a serious and potentially life-threatening medical complication occurring during pregnancy, is characterized by hypertension and often accompanied by proteinuria and multiorgan dysfunction. It is classified into two subtypes based on the timing of diagnosis: early-onset (EO-PE) and late-onset preeclampsia (LO-PE). Despite being less severe and exhibiting distinct pathophysiological characteristics, LO-PE is more prevalent than EO-PE, although both conditions have a significant impact on placental health. Previous research indicates that different pathophysiological events within the placenta may contribute to the development of preeclampsia across multiple pathways. In our experimental study, we investigated markers of oxidative stress, ferroptosis, and lipid peroxidation pathways in placental tissue samples obtained from women with LO-PE (n = 68) compared to healthy control pregnant women (HC, n = 43). Through a comprehensive analysis, we observed an upregulation of specific molecules associated with these pathways, including NADPH oxidase 1 (NOX-1), NADPH oxidase 2 (NOX-2), transferrin receptor protein 1 (TFRC), arachidonate 5-lipoxygenase (ALOX-5), acyl-CoA synthetase long-chain family member 4 (ACSL-4), glutathione peroxidase 4 (GPX4) and malondialdehyde (MDA) in women with LO-PE. Furthermore, increased ferric tissue deposition (Fe3+) was observed in placenta samples stained with Perls' Prussian blue. The assessment involved gene and protein expression analyses conducted through RT-qPCR experiments and immunohistochemistry assays. Our findings underscore the heightened activation of inflammatory pathways in LO-PE compared to HC, highlighting the pathological mechanisms underlying this pregnancy disorder.

Treatment with Rasburicase in Hospitalized Patients with Cardiorenal Syndrome: Old Treatment, New Scenario.

Cardiorenal syndrome (CRS) involves joint dysfunction of the heart and kidney. Acute forms share biochemical alterations like hyperuricaemia (HU) with tumour lysis syndrome (TLS). The mainstay treatment of acute CRS with systemic overload is diuretics, but rasburicase is used in TLS to prevent and treat hyperuricaemia. An observational, retrospective study was performed to assess the effectiveness and safety of a single dose of rasburicase in hospitalized patients with cardiorenal syndrome, worsening renal function and uric acid levels above 9 mg/dL. Rasburicase improved diuresis and systemic congestion in the 35 patients included. A total of 86% of patients did not need to undergo RRT, and early withdrawal was possible in the remaining five. Creatinine (Cr) decreased after treatment with rasburicase from a peak of 3.6 ± 1.27 to 1.79 ± 0.83 mg/dL, and the estimated glomerular filtration rate (eGFR) improved from 17 ± 8 to 41 ± 20 mL/min/1.73 m2 (p = 0.0001). The levels of N-terminal type B Brain Natriuretic Peptide (Nt-ProBNP) and C-reactive protein (CRP) were also significantly reduced. No relevant adverse events were detected. Our results show that early treatment with a dose of rasburicase in patients with CRS and severe HU is effective to improve renal function and systemic congestion, avoiding the need for sustained extrarenal clearance, regardless of comorbidities and ventricular function.

Exploring the Importance of Differential Expression of Autophagy Markers in Term Placentas from Late-Onset Preeclamptic Pregnancies.

Preeclampsia (PE) is a serious hypertensive disorder affecting 4-5% of pregnancies globally, leading to maternal and perinatal morbidity and mortality and reducing life expectancy in surviving women post-gestation. Late-onset PE (LO-PE) is a clinical type of PE diagnosed after 34 weeks of gestation, being less severe than the early-onset PE (EO-PE) variant, although both entities have a notable impact on the placenta. Despite the fact that most studies have focused on EO-PE, LO-PE does not deserve less attention since its prevalence is much higher and little is known about the role of the placenta in this pathology. Via RT-qPCR and immunohistochemistry methods, we measured the gene and protein expressions of several macroautophagy markers in the chorionic villi of placentas from women who underwent LO-PE (n = 68) and compared them to normal pregnancies (n = 43). We observed a markedly distinct expression pattern, noticing a significant drop in NUP62 expression and a considerable rise in the gene and protein expressions of ULK1, ATG9A, LC3, ATG5, STX-17, and LAMP-1 in the placentas of women with LO-PE. A major induction of autophagic processes was found in the placental tissue of patients with LO-PE. Abnormal signaling expression of these molecular patterns in this condition aids in the understanding of the complexity of pathophysiology and proposes biomarkers for the clinical management of these patients.

Placentas from Women with Late-Onset Preeclampsia Exhibit Increased Expression of the NLRP3 Inflammasome Machinery.

Pre-eclampsia is a harmful and potentially lethal medical condition during pregnancy clinically diagnosed by hypertension and commonly accompanied by proteinuria and multiorgan affections. According to the time of diagnosis, it is differentiated between early-onset (EO-PE) and late-onset preeclampsia (LO-PE). Despite being less dangerous and presenting distinct pathophysiological signatures, LO-PE has a greater prevalence than EO-PE, both having significant consequences on the placenta. Previous works have evidenced that exacerbated inflammation in this organ might play a potential pathogenic role in the development of pre-eclampsia, and there is some preliminary evidence that the hyperactivation of inflammasomes can be related to the altered immunoinflammatory responses observed in the placentas of these patients. However, the precise role of inflammasomes in the placentas of women with LO-PE remains to be fully understood. In this work, we have studied the gene and protein expression of the main components related to the canonical and non-canonical pathways of the inflammasome NLRP3 (NLRP3, ASC, caspase 1, caspase 5, caspase 8, interleukin 1ß, and interleukin 18) in the placental tissue of women with LO-PE. Our results show a marked increase in all these components in the placentas of women who have undergone LO-PE, suggesting that NLRP3 inflammasome plays a potentially pathophysiological role in the development of this entity. Future works should aim to evaluate possible translational approaches to this dysregulation in these patients.

Mortality Risk Prediction in Abdominal Septic Shock Treated with Polymyxin-B Hemoperfusion: A Retrospective Cohort Study.

Endotoxin, a component of the cell membrane of gram-negative bacteria, is a trigger for dysregulated inflammatory response in sepsis. Extracorporeal purification of endotoxin, through adsorption with polymyxin B, has been studied as a therapeutic option for sepsis. Previous studies suggest that it could be effective in patients with high endotoxin levels or patients with septic shock of moderate severity. Here, we perform a retrospective, single-centre cohort study of 93 patients suffering from abdominal septic shock treated with polymyxin-B hemoperfusion (PMX-HP) between 2015 and 2020. We compared deceased and surviving patients one month after the intervention using X2 and Mann-Whitney U tests. We assessed the data before and after PMX-HP with a Wilcoxon single-rank test and a multivariate logistic regression analysis. There was a significant reduction of SOFA score in the survivors. The expected mortality using APACHE-II was 59.62%, whereas in our sample, the rate was 40.9%. We found significant differences between expected mortality and real mortality only for the group of patients with an SOFA score between 8 and 13. In conclusion, in patients with abdominal septic shock, the addition of PMX-HP to the standard therapy resulted in lower mortality than expected in the subgroup of patients with intermediate severity of illness.

Tolvaptan in portal hypertension: real life experience.

Tolvaptan (TVP) is a selective antagonist of vasopressin receptors, approved for the treatment of hyponatremia in SIADH, congestive heart failure (CHF) and cirrhosis. We retrospectively reviewed all cases where TVP was used in a tertiary hospital (January 2012- January 2017). Our aim was to study the use of TVP in real life practice in patients with portal hypertension (PHT) (past history of non-malignant ascites or variceal bleed).

Mortality and renal long-term outcome of critically ill COVID-19 patients with acute kidney failure, continuous renal replacement therapy and invasive mechanical ventilation.

Background: There are limited data describing the long-term renal outcomes of critically ill COVID-19 patients with acute kidney injury (AKI) and continuous renal replacement therapy (CRRT) and invasive mechanical ventilation. Methods: In this retrospective observational study we analyzed the long-term clinical course and outcomes of 30 critically ill patients hospitalized with COVID-19 during the peak of highest incidence in the first wave, with acute respiratory distress syndrome (ARDS) and AKI that required CRRT. Baseline features, clinical course, laboratory data, therapies and filters used in CRRT were compared between survivors and non-survivors to identify risk factors associated with in-hospital death. Renal parameters: glomerular filtration rate, proteinuria and microhematuria were collected at 6 months after discharge. Results: 19 patients (63%) died and 11 were discharged. Mean time to death was 48 days (7-206) after admission. Patients with worse baseline renal function had higher mortality (P = 0.009). Patients were treated with CRRT for an average of 18.4 days. Filters with adsorptive capacity (43%) did not offer survival benefits. Regarding long-term renal outcomes, survivor patients did not receive any additional dialysis, but 9 out of 11 patients had an important loss of renal function (median of eGF of 44 (13-76) ml/min/1.73 m2) after 6 months. Conclusion: Mortality among critically ill hospitalized patients diagnosed with COVID-19 on CRRT is extremely high (63%). Baseline renal function is a predictor factor of mortality. Filters with adsorption capacity did not modify survival. None survivor patients required long-term dialysis, but an important loss of renal function occurred after AKI episode related to COVID-19 infection.

Introducción: La interacciónde COVID-19, ventilación mecánica invasiva (VMI) y fracaso renal agudo (FRA) con necesidad de terapia continua de reemplazo renal (TCRR) es conocida, pero hay pocos datos publicados sobre el pronóstico a largo plazo de este tipo de FRA. Métodos: Este estudio analiza los resultados a largo plazo de 30 pacientes ingresados en la UCI por neumonía por COVID-19, con VMI y FRA con TCRR en el pico de máxima incidencia. Comparamos las características basales, la evolución clínica y bioquímica y los diferentes filtros usados en la TCRR para identificar los factores de riesgo asociados a la muerte intrahospitalaria. Se analizaron el filtrado glomerular estimado (FGe), la proteinuria y la hematuria a los 6 meses de seguimiento de los supervivientes. Resultados: De los 30 pacientes, 19 fallecieron y 11 fueron dados de alta. Los pacientes con peor función renal tuvieron mayor mortalidad (p = 0,009). Los filtros usados con capacidad adsortiva no ofrecieron beneficios en cuanto a la supervivencia. De los 11 supervivientes, ninguno requirió terapia renal sustitutiva (TRS) una vez superada la infección, pero tuvieron una pérdida importante y mantenida en el tiempo de función renal (FGe de 44 ml/min/1,73 m2). Conclusión: La mortalidad en pacientes con neumonía por COVID-19 que requieren VMI y TCRR es extremadamente elevada (63%). Los filtros con capacidad adsortiva no modificaron la supervivencia. La función renal basal fue un factor predictor de mortalidad. En este tipo de FRA el deterioro de la función renal no se recupera, objetivándose una reducción importante del FGe a los 6 meses.

Mortality and renal long-term outcome of critically ill COVID-19 patients with acute kidney failure, continuous renal replacement therapy and invasive mechanical ventilation. / Mortalidad y función renal a largo plazo en pacientes ingresados en la UCI por COVID-19 con fracaso renal agudo, terapia continua de reemplazo renal y ventilación mecánica invasiva.

BACKGROUND: There are limited data describing the long-term renal outcomes of critically ill COVID-19 patients with acute kidney injury (AKI) and continuous renal replacement therapy (CRRT) and invasive mechanical ventilation. METHODS: In this retrospective observational study we analyzed the long-term clinical course and outcomes of 30 critically ill patients hospitalized with COVID-19 during the peak of highest incidence in the first wave, with acute respiratory distress syndrome (ARDS) and AKI that required CRRT. Baseline features, clinical course, laboratory data, therapies and filters used in CRRT were compared between survivors and non-survivors to identify risk factors associated with in-hospital death. Renal parameters: glomerular filtration rate, proteinuria and microhematuria were collected at 6months after discharge. RESULTS: 19 patients (63%) died and 11 were discharged. Mean time to death was 48days (7-206) after admission. Patients with worse baseline renal function had higher mortality (P=.009). Patients were treated with CRRT for an average of 18.4days. Filters with adsorptive capacity (43%) did not offer survival benefits. Regarding long-term renal outcomes, survivor patients did not receive any additional dialysis, but 9 out of 11 patients had an important loss of renal function (median of eGF of 44 (13-76)ml/min/1.73m2) after 6months. CONCLUSION: Mortality among critically ill hospitalized patients diagnosed with COVID-19 on CRRT is extremely high (63%). Baseline renal function is a predictor factor of mortality. Filters with adsorption capacity did not modify survival. None survivor patients required long-term dialysis, but an important loss of renal function occurred after AKI episode related to COVID-19 infection.

Maternal-Perinatal Variables in Patients with Severe Preeclampsia Who Develop Acute Kidney Injury.

Introduction: At present, we are witnessing an increase in preeclampsia, especially the most severe forms, which are associated with an increased risk of maternal-perinatal morbidity and mortality. As a severity criterion, acute kidney injury (AKI) has been associated with a worse prognosis, and for this reason, the maternal and perinatal variables associated with AKI in patients with severe preeclampsia (SP) were analysed in this study. Methods: An observational, retrospective, single-centre study of patients with SP treated at a tertiary hospital between January 2007 and December 2018 was conducted. The case criteria based on the criteria established by the ACOG Practice Guidelines for Gestational Hypertension and Preeclampsia. AKI is considered when serum creatinine exceeds 1.1 mg/dL in a pregnant woman with previously normal renal function. In patients with existing chronic kidney disease (CKD), it is referred to as AKI if the baseline serum creatinine increases by 1.5 fold. Pregestational, gestational and postpartum variables were analysed up to 12 weeks postpartum using univariate and multivariate logistic regression analysis. Results: During the study period, 76,828 births were attended, and 303 pregnant women were diagnosed with SP. The annual incidence of SP increased gradually throughout the study period, reaching 1.79/100 births/year in 2018. Acute kidney injury (AKI) occurred in 24.8% of the patients. The multivariate analysis revealed an increased association with a history of previous CKD, the use of assisted reproductive techniques and caesarean section. Uric acid and thrombotic microangiopathy (TMA) had a high correlation with AKI. Indications for caesarean section are associated with AKI in SP. Regarding perinatal outcomes in cases of AKI, there was a higher percentage of neonates who required foetal lung maturation with steroids and an increased need for NICU admission. No case of maternal death was recorded; however, an increase in neonatal mortality was found among patients who did not develop AKI. After 12 weeks postpartum, 72 patients were referred to the nephrology consultation for persistent hypertension, proteinuria or renal failure. Conclusions: In preeclampsia, AKI is a common complication, especially among patients with a history of CKD, those who became pregnant using assisted reproduction techniques and those who delivered via caesarean section. The perinatal impact of AKI is mainly centred on a higher rate of NICU admission and a lower mortality rate. Among biochemical and haematological markers, the uric acid level prior to renal failure has a direct and significant correlation with the risk of AKI, as does the development of TMA in patients with preeclampsia. Therefore, the monitoring of renal function in cases of preeclampsia should be strict, and referral for a nephrology consultation may be necessary in some cases.

Maternal Perinatal Characteristics in Patients with Severe Preeclampsia: A Case-Control Nested Cohort Study.

Preeclampsia is one of the most worrisome complications during pregnancy, affecting approximately 1 out of 20 women worldwide. Preeclampsia is mainly characterized by a sustained hypertension, proteinuria, also involving a significant organ dysfunction. Moreover, 25% of the cases could be classified as severe preeclampsia (SP), a serious condition that could be life-threatening for both the mother and fetus. Although there are many studies focusing on preeclampsia, less efforts have been made in SP, frequently limited to some specific situations. Thus, the present study aims to conduct a comparative analysis of risk factors, maternal characteristics, obstetric and neonatal outcomes and maternal complications in patients with severe preeclampsia versus patients without severe preeclampsia. Hence, 235 cases and 470 controls were evaluated and followed in our study. We described a set of variables related to the development of severe preeclampsia, including maternal age > 35 years (69.8%), gestational (26.8%) or chronic arterial hypertension (18.3%), obesity (22.6%), use of assisted reproduction techniques (12.3%), prior history of preeclampsia (10.2%) and chronic kidney disease (7.7%) All patients had severe hypertension (>160 mmHg) and some of them presented with additional complications, such as acute renal failure (51 cases), HELLP syndrome (22 cases), eclampsia (9 cases) and acute cerebrovascular accidents (3 cases). No case of maternal death was recorded, although the SP group had a higher cesarean section rate than the control group (60% vs. 20.9%) (p < 0.001), and there was a notably higher perinatal morbidity and mortality in these patients, who had a prematurity rate of 58.3% (p < 0.001) and 14 perinatal deaths, compared to 1 in the control group. Overall, our study recognized a series of factors related to the development of SP and related complications, which may be of great aid for improving the clinical management of this condition.

Metformin-associated acute kidney injury and lactic acidosis.

Objectives. Metformin is the preferred oral antidiabetic agent for type 2 diabetes. Lactic acidosis is described as a rare complication, usually during an acute kidney injury (AKI). Material and Methods. We conducted a prospective observational study of metformin-associated AKI cases during four years. 29 cases were identified. Previous renal function, clinical data, and outcomes were recorded. Results. An episode of acute gastroenteritis precipitated the event in 26 cases. Three developed a septic shock. Three patients died, the only related factor being liver dysfunction. More severe metabolic acidosis hyperkalemia and anemia were associated with higher probabilities of RRT requirement. We could not find any relationship between previous renal dysfunction and the outcome of the AKI. Conclusions. AKI associated to an episode of volume depletion due to gastrointestinal losses is a serious complication in type 2 diabetic patients on metformin. Previous renal dysfunction (mild-to-moderate CKD) has no influence on the severity or outcome.

Inflammatory syndrome in patients on hemodialysis.

Mortality is markedly elevated in hemodialysis (HD) patients. Between 30 and 50% of prevalent patients have elevated serum levels of inflammatory markers such as C-reactive protein and IL-6. The presence of inflammation, chronic or episodic, has been found to be associated with increased mortality risk. The causes of inflammation are multifactorial and include patient-related factors, such as underlying disease, comorbidity, oxidative stress, infections, obesity, and genetic or immunologic factors, or on the other side, HD-related factors, mainly depending on the membrane biocompatibility and dialysate quality. The adequate knowledge of these causes and their prevention or treatment if possible may contribute to improving the inflammatory state of patients who are on HD and possibly their mortality.

Interdialytic weight gain as a marker of blood pressure, nutrition, and survival in hemodialysis patients.

BACKGROUND: Excessive interdialytic weight gain (IDWG) is usually related to an overload of sodium and water, and is the most important factor for arterial hypertension in dialysis. On the other hand, food intake also contributes to IDWG, and is the basic factor for nutrition. The objective of this study is to assess the long-term prognostic effect of IDWG and its relationship with the nutritional status and blood pressure in patients in hemodialysis (HD). METHODS: We describe the results of a 5-year prospective observation study in which 134 HD patients were included (70 males and 64 females), with ages between 18 and 81. Initially, the average data were collected during 4 weeks, including total IDWG and percentages according to dry weight (IDWG%), nutritional parameters, and blood pressure. Patients were divided into 3 cohorts according to IDWG% (<2.9, 2.9-3.9, and >3.9%, respectively). Student t test, ANOVA, linear regression analysis, and Kaplan-Meier survival curves compared with log-rank test were used as statistical tools. RESULTS: The mean IDWG% for the whole studied population was 3.5 +/- 1.1% (1.5-8.0%). It was not related to gender, but had an inverse correlation with age (P < 0.000) and serum bicarbonate level (P= 0.009). It was directly correlated with predialysis systolic and diastolic blood pressure, nPCR, urea and creatinine levels (P < 0.01 for all of them), and the body mass index (P < 0.000). Serum levels of albumin (44.7 +/- 4.0 g/dL) and prealbumin (31.9 +/- 7.4 mg/dL) had a direct correlation with total IDWG (P < 0.01). We found no significant relationship between or IDWG% and ferritin and transferrin levels. Five-year actuarial survival was 0.38, 0.52, and 0.63, respectively, in the 3 cohorts for IDWG% (P < 0.01). CONCLUSION: Our results show that a greater IDWG is directly associated with a better nutritional status, although it is also associated with higher predialysis blood pressure. The greater the IDWG%, the better the long-term prognosis of the patients. The beneficial effects of IDWG on the nutritional status and prognosis are greater than the negative aspects that depend on its effects on blood pressure. One must distinguish clearly between some isolated instances of not complying with a diet from those situations where a higher IDWG is merely a reflection of a good nutritional status, and one must be careful so that dietary recommendations will not have a negative influence on nutritional aspects. One must watch and correct the trend towards higher acidosis in patients with a greater IDWG.

Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance.

Patients returning to hemodialysis (HD) after failure of their kidney transplant suffer from high morbidity and mortality rates. It is common practice to keep failed kidney transplants in place. It is not known if these failed kidney transplants induce an inflammatory state that contributes to morbidity and mortality. In a single facility, patients starting on HD with failed kidney transplant were identified (Group A) and screened for the presence of chronic inflammatory state. Those with clinical symptoms attributed to the failed allograft (Group A1) were not offered transplant nephrectomy unless deemed necessary during follow-up. Their clinical and laboratory data were followed up for 6 months. Similar data were obtained from a group of incident HD patients (Group B). Forty-three patients had a failed Kidney transplant (Group A). Of these, 29 comprised Group A1 and 14 Group A2. Group B comprised 121 patients. In comparison with Group B, Group A exhibited worse anemia and erythropoietin resistance index (ERI), had lower serum albumin and prealbumin, and higher CRP. Group A1 had lower Hb and higher ferritin, CRP, and ESR in comparison with Group A2. Following transplant nephrectomy, Group A1 had improvement in ERI, serum albumin, prealbumin, ferritin, fibrinogen, CRP, and ESR. At 6 months, Group A1 had higher Hb and serum albumin levels, and lower CRP and ERI in comparison with Group A2. Group B parameters showed no change during follow-up. Patients returning to HD following failure of their kidney transplant suffer from a chronic inflammatory state. Resection of failed transplants in symptomatic patients is associated with amelioration of markers of chronic inflammation. Transplant nephrectomy should be considered a treatment option for patients with failed kidney transplants, especially if they exhibit signs and symptoms of chronic inflammatory state.

Parathyroidectomy: whom and when?

Hyperparathyroidism (HPT) is common in patients on dialysis, and parathyroidectomy (PTx) is often required. We present a retrospective, descriptive analysis of data corresponding to 148 patients on dialysis undergoing PTx due to severe refractory HPT (PTH 1401 +/- 497 pg/mL, Ca 10.6 +/- 0.8 mg/dL, P 6.9 +/- 1.7 mg/dL). Demographic data were compared with those recorded in 309 patients on dialysis not subjected to PTx who were managed at the same hospital. In the PTx group, the factors age (49.3 +/- 14 years), male gender (48.6%), and diabetes (0.7%) were significantly lower than in the non-PTx group (61.5 +/- 14.9 years, male gender 59%, diabetes 19.4%), while time on dialysis was longer (8.6 +/- 5.8 vs. 5.5 +/- 5.4 years). In 129 of the study patients (87.4%), four or more glands were identified, and total PTx plus autotransplantation (AT) in the forearm was performed. In the remaining 19 patients, two to three glands were identified, and AT was not undertaken. Four of the 19 patients were successfully operated on again for persistent HPT, seven showed PTH levels <250 pg/mL, and eight maintained severe HPT. Perioperative complications included one death due to cardiac insufficiency, two repeat operations due to bleeding, and one patient with chronic hoarseness. Hospital stay was prolonged in 20% of patients due to a hungry bone syndrome. Among those patients with PTx and AT, HPT recurred in 21 patients (16.2%) at 3.1 +/- 2.3 years. In 13 of these patients, autograft was removed at 7.5 +/- 2.9 years. Serum calcium and phosphate levels improved after PTx, and these results were maintained for 5 years (9.6 +/- 0.8 and 4.2 +/- 1.2 mg/dL, respectively). In conclusion, PTx with AT is a safe option for the treatment of severe HPT that is accompanied by low morbidity and mortality and a good outcome. Medical treatment should not be prolonged at the expense of long repeated bouts of hypercalcemia and/or hyperphosphatemia with their irreversible consequences.