Search

Acute kidney injury (AKI) commonly occurs in patients with decompensated cirrhosis. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) could help discriminate between different etiologies of AKI. The aim of this study was to investigate the use of uNGAL in (1) the differential diagnosis of AKI, (2) predicting the response to terlipressin and albumin in patients with hepatorenal syndrome-AKI (HRS-AKI), and (3) predicting in-hospital mortality in patients with AKI.One hundred sixty-two consecutive patients with cirrhosis and AKI were included from 2015 to 2020 and followed until transplant, death, or 90 days. Standard urinary markers and uNGAL were measured. Data on treatment, type, and resolution of AKI were collected. Thirty-five patients (21.6%) had prerenal AKI, 64 (39.5%) HRS-AKI, 27 (16.7%) acute tubular necrosis-AKI (ATN-AKI), and 36 (22.2%) a mixed form of AKI. Mean values of uNGAL were significantly higher in ATN-AKI than in other types of AKI (1162 ng/ml [95% CI 423-2105 ng/ml] vs. 109 ng/ml [95% CI 52-192 ng/ml]; p 0.001). uNGAL showed a high discrimination ability in predicting ATN-AKI (area under the receiver operating characteristic curve, 0.854; 95% CI 0.767-0.941; p 0.001). The best-performing threshold was found to be 220 ng/ml (sensitivity, 89%; specificity, 78%). The same threshold was independently associated with a higher risk of nonresponse (adjusted OR [aOR], 6.17; 95% CI 1.41-27.03; p = 0.016). In multivariable analysis (adjusted for age, Model for End-Stage Liver Disease, acute-on-chronic liver failure, leukocytes, and type of AKI), uNGAL was an independent predictor of in-hospital mortality (aOR, 1.74; 95% CI 1.26-2.38; p = 0.001).uNGAL is an adequate biomarker for making a differential diagnosis of AKI in cirrhosis and predicting the response to terlipressin and albumin in patients with HRS-AKI. In addition, it is an independent predictor of in-hospital mortality.

Osteopontin (OPN) is a phosphoglycoprotein secreted into the extracellular matrix upon liver injury, acting as a cytokine stimulates the deposition of fibrillary collagen in liver fibrogenesis. In livers of mice subjected to bile duct ligation (BDL) and in cultured activated hepatic stellate cells (HSCs), we show that OPN, besides being overexpressed, is substantially phosphorylated by family with sequence similarity 20, member C (Fam20C), formerly known as Golgi casein kinase (G-CK), which is exclusively resident in the Golgi apparatus. In both experimental models, Fam20C becomes overactive when associated with a 500-kDa multiprotein complex, as compared with the negligible activity in livers of sham-operated rats and in quiescent HSCs. Fam20C knockdown not only confirmed the role of Fam20C itself in OPN phosphorylation, but also revealed that phosphorylation was essential for OPN secretion. However, OPN acts as a fibrogenic factor independently of its phosphorylation state, as demonstrated by the increased expression of Collagen-I by HSCs incubated with either a phosphorylated or nonphosphorylated form of recombinant OPN. Collectively, our results confirm that OPN promotes liver fibrosis and highlight Fam20C as a novel factor driving this process by favoring OPN secretion from HSCs, opening new avenues for deciphering yet unidentified mechanisms underlying liver fibrogenesis.

Acute decompensation (AD) of cirrhosis may present without acute-on-chronic liver failure (ACLF) (AD-No ACLF), or with ACLF phenotype (AD-ACLF) defined by organ failure(s). Precipitants may induce AD. This multicenter, prospective, observational PREDICT study (NCT03056612) analyzes and characterizes the precipitants leading to both of these AD phenotypes., info:eu-repo/semantics/published

In liver cirrhosis, oxidative stress plays a major role in promoting liver inflammation and fibrosis. Mitochondria dysregulation is responsible for excessive reactive oxygen species production. Therefore, in an experimental model of cirrhosis, we investigated the effect of mitochondria-targeted antioxidant mitoquinone. Liver cirrhosis was induced in Spraque-Dawley rats by common bile duct ligation (CBDL). Mitoquinone (10 mg·kg−1·day−1, oral gavage) or vehicle was administered from 3rd to 28th day after CBDL, when animals were euthanized; liver oxidative stress, inflammation, fibrosis, mitophagy were evaluated; and in vivo and ex vivo hemodynamic studies were performed. In cirrhotic rats, mitoquinone prevented liver inflammation, hepatocyte necrosis, and fibrosis at histological examination; decreased circulating TNF-α, gene expression of transforming growth factor-β1, collagen type 1a1, TNF-α, IL-6, IL-1β, tissue inhibitor of metalloproteinase-1, matrix metalloproteinase (MMP)-2, and MMP-13; and reduced hepatic oxidative stress, as shown by reduced oxidative carbonylation of the proteins, by modulating antioxidants catalase, Mn superoxide dismutase, and Cu/Zn superoxide dismutase. Furthermore, mitoquinone attenuated apoptosis by reducing hepatic protein expression of cleaved caspase-3. A selective removal of dysfunctional mitochondria was improved by mitoquinone, as shown by the increase in Parkin translocation to mitochondria. Treatment with mitoquinone normalized the weight of the spleen; however, it increased portal blood flow and reduced splenic artery intrahepatic resistance, suggesting an effect on resistance index. Mitochondria-targeted antioxidant mitoquinone improves liver inflammation and fibrosis in cirrhotic rats by reducing hepatic oxidative stress, preventing apoptosis, and promoting removal of dysfunctional mitochondria. Therefore, it may represent a promising strategy for the prevention and treatment of liver cirrhosis.

Acute decompensation (AD) of cirrhosis is defined as the acute development of ascites, gastrointestinal hemorrhage, hepatic encephalopathy, infection or any combination thereof, requiring hospitalization. The presence of organ failure(s) in patients with AD defines acute-on-chronic liver failure (ACLF). The PREDICT study is a European, prospective, observational study, designed to characterize the clinical course of AD and to identify predictors of ACLF., info:eu-repo/semantics/published

Background & Aims Relative adrenal insufficiency (RAI) is defined by insufficient production of cortisol relative to organ demand. RAI is observed frequently in hospitalized patients with cirrhosis, but there is disagreement over the clinical effects of RAI in these patients. We evaluated the prevalence and the clinical effects of RAI in hospitalized patients with cirrhosis. Methods We performed a prospective study of 160 patients admitted to a hospital in Italy for acute decompensation of cirrhosis from May 2011 through September 2016. Patients were followed up until death, liver transplantation, or a maximum of 90 days. Serum and salivary levels of cortisol were measured before and after a 1-hour Short Synacthen Test. A diagnosis of RAI was given to patients with an increase in serum cortisol of less than 9 μg/dL, after Synacthen administration, in patients with baseline serum levels of cortisol less than 35 μg/dL. We collected blood samples before the Synacthen test and analyzed them for blood cell counts, liver and renal function, levels of C-reactive protein, and lipid profiles (total cholesterol, high-density lipoprotein cholesterol, apolipoprotein-A1). Results A diagnosis of RAI was made for 78 patients (49%). Age (odds ratio [OR], 0.95; P = .030), number of leukocytes (OR, 3.10; P = .006), and levels of high-density lipoprotein cholesterol (OR, 0.30; P = .039) were associated independently with RAI. Patients with RAI had a significantly higher risk of developing bacterial infections (hazard ratio [HR], 1.60; P = .038), sepsis (HR, 2.95; P = .001), septic shock (HR, 4.94; P = .038), new organ failures (HR, 2.45; P = .014), and acute-on-chronic liver failure (HR, 2.27; P = .037) than patients without RAI. RAI was associated independently with death within 90 days of diagnosis (subdistribution HR, 4.83; P = .001). Patients with RAI and mild renal dysfunction or hepatic encephalopathy had no significant difference in cumulative incidence of 28-day mortality vs patients with acute-on-chronic liver failure grade 1 (25% vs 22%). Conclusions We found RAI to occur in almost half of patients admitted to a hospital for acute decompensation of cirrhosis. RAI was associated with a deficit of substrates for steroidogenesis and an increase in markers of inflammation. Patients with RAI have a high risk of developing sepsis, septic shock, organ failure, and death within 90 days. RAI has similar prognostic value to nonrenal organ failures.

Patients with cirrhosis have a high prevalence of renal dysfunction. The susceptibility to renal dysfunction is due to both the severe splanchnic arterial vasodilation and the systemic inflammation observed in these patients. An accurate assessment of renal function is recommended in all patients with cirrhosis. Indeed, the renal function assessment guides the management of patients, helps to refine prognosis and to define transplant strategies. Despite its limitations, serum creatinine is still the most used biomarker for the estimation of glomerular filtration rate (GFR) and the assessment of acute kidney injury (AKI) in patients with cirrhosis. New biomarkers of GFR such as cystatin C may improve the assessment of GFR and the prognostic stratification in these patients. AKI is a life-threatening complication and needs a timely management. The differential diagnosis between hepatorenal syndrome (HRS) and acute tubular necrosis (ATN) is tricky in clinical practice. New biomarkers of kidney injury, such as neutrophil gelatinase-associated lipocalin and interleukin-18, represent useful tools in refining the discrimination between HRS and ATN. Patients with HRS need a prompt treatment with vasoconstrictors and albumin and a rapid evaluation for liver transplant eligibility. In this article, the authors reviewed the available tools in the diagnosis and management of renal dysfunction in cirrhosis.

Introduction Mental stress is potentially a major cardiovascular risk factor. Meditation and listening to music may be able to compensate by eliciting the Relaxation Response (RR) with a beneficial prognostic impact after myocardial infarction (MI), reducing the progression of the arteriosclerotic process and improving coronary blood flow. We aimed to study a possible epigenetic mechanism of the RR speculating that circulating microRNAs levels could change during relaxation. Methods We enrolled 150 consecutive patients after MI. 50 were trained to meditate, 50 given music appreciation and 50 served as controls. In addition, in order to rule out that the disease state could interfere with the possible movement of microRNAs, we enrolled 50 healthy volunteers (25 were trained to meditate and 25 had music appreciation). After training, and after 60 days of RR practice, we studied the individual variation, before and after the relaxation session, of some important cardiovascular circulating microRNAs: the microRNA-1, −16, −24, −33, −92, −144, −146, −155. Results As the RR appeared to be triggered in the same way irrespective of whether this was by music or meditation data was combined. After the RR, a reduction in microRNA-16, −33, −92, −144, −146, −155 (p Conclusions The RR modulates some microRNAs levels suggesting that psychic activity may be an important epigenetic and pathophysiological factor in the arteriosclerotic process and in ischemic heart disease. In particular, the analyzed microRNAs levels seems to vary in relation to the state of stress or relaxation of the subjects.

Background Mental stress is one of the main risk factors for cardiovascular disease. Meditation and music listening are two techniques that are able to counteract it through the activation of specific brain areas, eliciting the so-called Relaxing Response (RR). Epidemiological evidence reveals that the RR practice has a beneficial prognostic impact on patients after myocardial infarction. We aimed to study the possible molecular mechanisms of RR underlying these findings. Methods We enrolled 30 consecutive patients after myocardial infarction and 10 healthy controls. 10 patients were taught to meditate, 10 to appreciate music and 10 did not carry out any intervention and served as controls. After training, and after 60 days of RR practice, we studied the individual variations, before and after the relaxation sessions, of the vital signs, the electrocardiographic and echocardiographic parameters along with coronary flow reserve (CFR) and the carotid's intima media thickness (IMT). Neuro-endocrine-immune (NEI) messengers and the expression of inflammatory genes (p53, Nuclear factor Kappa B (NfKB), and toll like receptor 4 (TLR4)) in circulating peripheral blood mononuclear cells were also all observed. Results The RR results in a reduction of NEI molecules (p, Graphical abstract Image 1

Background: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Its pathophysiology is complex and not completely understood. In this study, we examined the role of apoptosis and the caspase pathways involved. Material and Methods: We enrolled 40 acute heart failure (AHF) patients, 11 of whom developed AKI characterizing CRS type 1. We exposed the human cell line U937 to plasma from the CRS type 1 and AHF groups and then we evaluated apoptotic activity by annexin-V evaluation, determination of caspase-3, -8 and -9 levels, and BAX, BAD, and FAS gene expression. Results: We observed significant upregulation of apoptosis in monocytes exposed to CRS type 1 plasma compared to AHF, with increased levels of caspase-3 (p < 0.01), caspase-9 (p < 0.01), and caspase-8 (p < 0.03) showing activation of both intrinsic and extrinsic pathways. Furthermore, monocytes exposed to CRS type 1 plasma had increased gene expression of BAX and BAD (intrinsic pathways) (p = 0.010 for both). Furthermore, strong significant correlations between the caspase-9 levels and BAD and BAX gene expression were observed (Spearman ρ = – 0.76, p = 0.011, and ρ = – 0.72, p = 0.011). Conclusion: CRS type 1 induces dual apoptotic pathway activation in monocytes; the two pathways converged on caspase-3. Many factors may induce activation of both intrinsic and extrinsic apoptotic pathways in CRS type 1 patients, such as upregulation of proinflammatory cytokines and hypoxia/ischemia. Further investigations are necessary to corroborate the present findings, and to better understand the pathophysiological mechanism and consequent therapeutic and prognostic implications for CRS type 1.

In patients with cirrhosis, infections represent a frequent trigger for complications, increasing frequency of hospitalizations and mortality rate. This study aimed to identify predictors of early readmission (30 days) and of mid-term mortality (6 months) in patients with liver cirrhosis discharged after a hospitalization for bacterial and/or fungal infection.A total of 199 patients with cirrhosis discharged after an admission for a bacterial and/or fungal infection were included in the study and followed up for a least 6 months.During follow-up, 69 patients (35%) were readmitted within 30 days from discharge. C-reactive protein (CRP) value at discharge (odds ratio (OR)=1.91; P=0.022), diagnosis of acute-on-chronic liver failure during the hospital stay (OR=2.48; P=0.008), and the hospitalization in the last 30 days previous to the admission/inclusion in the study (OR=1.50; P=0.042) were found to be independent predictors of readmission. During the 6-month follow-up, 47 patients (23%) died. Age (hazard ratio (HR)=1.05; P=0.001), model of end-stage liver disease (MELD) score (HR=1.13; P0.001), CRP (HR=1.85; P=0.001), refractory ascites (HR=2.22; P=0.007), and diabetes (HR=2.41; P=0.010) were found to be independent predictors of 6-month mortality. Patients with a CRP10 mg/l at discharge had a significantly higher probability of being readmitted within 30 days (44% vs. 24%; P=0.007) and a significantly lower probability of 6-month survival (62% vs. 88%; P0.001) than those with a CRP ≤10 mg/l.CRP showed to be a strong predictor of early hospital readmission and 6-month mortality in patients with cirrhosis after hospitalization for bacterial and/or fungal infection. CRP values could be used both in the stewardship of antibiotic treatment and to identify fragile patients who deserve a strict surveillance program.

Background: Cardiac surgery–associated acute kidney injury is a frequent and serious postoperative complication of cardiac surgery and is associated with an increased risk of morbidity, mortality, and length stay. In this study, we hypothesized that persistent elevation in inflammation in the first 48 h might be a powerful predictor of clinical outcome. Our aim was to elucidate the usefulness of interleukin-6 and procalcitonin postoperative levels in predicting mortality and renal complications in cardiac surgery patients. Methods: A total of 122 cardiac surgery patients were enrolled. Procalcitonin and interleukin-6 concentrations were measured on the second postoperative day, and their levels were evaluated versus a number of conditions and endpoints. Results: Procalcitonin has a good predictive value for adverse renal outcome (p Conclusion: We speculated that procalcitonin and interleukin-6 could be two effective biomarkers. There is a possibility of having a combined inflammatory multi-biomarker panel, with procalcitonin for predicting renal outcome and interleukin-6 for predicting mortality.

Background: Hemolytic uremic syndrome (HUS) can be triggered by Shiga toxin producing Escherichia coli (STEC) infection or it can be defined as atypical HUS (aHUS) if it is related to uncontrolled complement activation. aHUS is characterized by a high incidence of recurrence after kidney transplantation, and it can also occur de novo in transplant recipients. Eculizumab is used both to prevent and to treat aHUS following kidney transplantation. In this paper, we report our centre experience and we present 4 cases of HUS in patients who underwent kidney transplantation. Methods: This is a single-center experience about HUS development in transplanted patients. Results: Patient 1 with end-stage renal disease (ESRD) due to STEC-HUS undergoing kidney transplantation without prophylactic therapy with eculizumab. Patient 2 with HUS secondary to an episode of diarrhea at 8 years old. After a slow progression to ESRD, she underwent kidney transplantation and she received prophylactic therapy with eculizumab due to the presence of anti-complement factor H antibodies. Patient 3 underwent pre-emptive living donor ABO-incompatible kidney transplantation and developed HUS secondary to antibody-mediated rejection. Patient 4 developed de novo HUS 16 years after kidney transplantation without a known cause. Conclusion: The correct diagnosis of HUS and the identification of the complement component alterations in case of aHUS are important parameters required to predict the risk of post-transplant recurrence of the disease. In the cases we reported, eculizumab has been found to be effective both to prevent and to treat aHUS following kidney transplantation.

Lipopolysaccharide or endotoxin, the major cell wall component of gram-negative bacteria, plays a pivotal role in the pathogenesis of sepsis. It is able to activate the host defense system through the interaction with Toll-like receptor 4, thus triggering pro-inflammatory mechanisms. When the production of inflammatory mediators becomes uncontrolled and excessive, septic shock develops with multiple organ dysfunction, such as myocardial and renal impairment, which are hallmarks of cardiorenal syndrome type 5. In this review, we will analyze the role of endotoxin in the pathogenesis of sepsis, its effects on cardiac and renal interactions in the setting of cardiorenal syndrome type 5 and the possible use of extracorporeal therapies in this clinical condition.

Gram-negative sepsis is a major cause of morbidity and mortality in critical ill patients. Recent findings in molecular biology and in signaling pathways have enhanced our understanding of its pathogenesis and opened up opportunities of innovative therapeutic approaches. Endotoxin plays a pivotal role in the pathogenesis of multi-organ dysfunction in the setting of gram-negative sepsis. Indeed, heart and kidney impairments seem to be induced by the release of circulating pro-inflammatory and pro-apoptotic mediators triggered by endotoxin interaction with immune cells. These molecules are responsible for cellular apoptosis, autophagy, cell cycle arrest, and microRNAs activation. Therefore, the early identification of sepsis-associated acute kidney injury and heart dysfunction may improve the patient clinical outcome. In this report, we will consider the role of endotoxin in the pathogenesis of sepsis, its effects on both cardiac and renal functions, and the interactions between these 2 systems in the setting of cardiorenal syndromes (CRS), particularly in CRS type 5. Finally, we will discuss the possible role of extracorporeal therapies in reducing endotoxin levels.

Background: In living kidney transplantation, preoperative donors' renal functional reserve (RFR) may correlate with postoperative residual renal function in both donors and recipients. The aim of this study was to evaluate the donors' RFR before transplantation and to compare basal and stress renal function before and after transplantation in both donors and recipients. Methods: Seven pairs of living kidney donors and recipients were considered for this observational study. RFR was measured with a renal stress test (RST) before and after the kidney transplantation through an oral protein loading test (1 g/kg of body weight). RFR was defined as the difference between the maximum value of creatinine clearance after protein load (stress glomerular filtration rate, sGFR) and baseline creatinine clearance (basal GFR, bGFR). Results: Before transplantation, a significant difference between sGFR and bGFR (p = 0.04) was observed in donors, with an RFR = 30.6 (11.9-41.5) mL/min/1.73 m2. After kidney transplantation, sGFR was similar to bGFR for both donors and recipients (p = 0.13), with a limited RFR (7.9 [6.70-19.25] and 14.90 [-6.67 to 25.53] mL/min/1.73 m2, respectively). The sum of the donor's and recipient's post-transplant sGFR was similar to the pre-transplant donor's sGFR (p = 0.73). Conclusion: RST is a safe, feasible, easy, and an inexpensive tool that is able to quantify RFR. In living kidney transplantation, it can be used in clinical practice to measure the original global filtration capacity of the donor's kidneys (sGFR) and to quantify the susceptibility of donors and recipients in developing postoperative kidney dysfunction. However, further studies with an adequate sample size and follow-up period are needed to test this hypothesis.

The hemolytic uremic syndrome (HUS) is one of the thrombotic microangiopathies and it consists of the triad of nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The atypical form of HUS (aHUS) is related to causative mutations in complement genes. Some conditions act as a trigger for aHUS in individuals that have a genetic background predisposing to complement activation. Interferon β is a recombinant-protein therapy approved to treat multiple sclerosis (MS), and can be a causative agent in the occurrence of HUS through anti-angiogenic activity. In this paper, we briefly review aHUS clinical and genetic characteristics. Furthermore, we present a case of a 48-year-old woman, diagnosed with MS and treated with INFβ-1b from 2008. In December 2015, she presented with asthenia and loss of muscular strength in the legs and she quickly developed aHUS. Our case suggests that INFβ is a possible triggering factor for HUS.

Background/Aims: Cardiorenal Syndrome Type 5 (CRS Type 5) is characterized by concomitant cardiac and renal dysfunction in the setting of different systemic disorders, such as sepsis. In this study, we investigated the possible relationship between endotoxin levels, renal cell death and inflammation in septic patients with CRS Type 5. Methods: We enrolled 11 patients with CRS Type 5. CRS Type 5 was defined according to the current classification system. AKI was defined by Acute Kidney Injury Network (AKIN) criteria. Acute cardiac dysfunction was documented by echocardiography as acute left and/or right ventricular dysfunction leading to decreased ejection fraction. Endotoxin activity was measured by the Endotoxin Activity Assay (EAA). Plasma from CRS Type 5 patients was incubated with renal tubular cells (RTCs) and cell death levels were evaluated. Plasma cytokines levels were measured as well. Results: Accordingly to EAA levels, patients were divided into two groups: 45.4% of patients had low endotoxin activity level (negative EAA), while 54.5% of patients showed high endotoxin activity (positive EAA). RTCs incubated with plasma from EAA positive patients showed significantly higher apoptosis levels and higher caspase-3 activation compared to cells incubated with plasma from EAA negative patients, and a significant positive correlation was observed between EAA levels and RTC apoptosis levels. Furthermore, IL-6 and IFN-γ levels were significantly higher in CRS Type 5 patients with positive EAA. Conclusion: Our data suggest a possible relationship between endotoxin levels and renal cell death in septic patients with CRS Type 5. Furthermore, this study highlights the presence of renal apoptosis, the immune deregulation and the strong inflammation in CRS Type 5 patients, especially in those with high endotoxin activity.

Ascites has been classified according to quantity and response to medical therapy. Despite its precise definitions, little is known about the effects of grade 1 ascites or recurrent ascites (i.e. ascites that recurs at least on 3 occasions within a 12-month period despite dietary sodium restriction and adequate diuretic dosage) on patient outcome. We studied progression of grade 1 ascites and recurrent ascites in a large cohort of outpatients with cirrhosis.We performed a post-hoc analysis of data from 547 outpatients with cirrhosis (259 without ascites, 54 patients with grade 1 ascites, 234 with grade 2 or 3 ascites) who participated a care management program study in Italy from March 2003 through September 2017. We collected demographic, clinical, and laboratory data and patients were evaluated at least every 6 months. Patients received abdominal ultrasound analysis at study inclusion and at least twice a year. Number and volume of paracentesis were collected, when available. Patients were followed until death, liver transplantation, or March 2018. The median follow-up time was 29 months. Primary outcomes were mortality and development of complications of cirrhosis.There was no significant difference in 60-month transplant-free survival between patients with grade 1 vs grade 2 or 3 ascites (36% vs 43%) but survival was significantly lower when both groups were compared with patients without ascites (68%; P.001 for both comparisons). However, the grade of systemic inflammation and the rate of complications were significantly greater in patients with grade 1 ascites than in patients without ascites, but significantly lower than in patients with grade 2 or 3 ascites. Development of grade 2 or 3 ascites did not differ significantly between patients with no ascites vs grade 1 ascites (10% vs 14%). There was no significant difference in 36-month transplant-free survival between patients with ascites responsive to medical treatment vs recurrent ascites (78% vs 62%), whereas patients with refractory ascites had significantly lower survival than patients with responsive or recurrent ascites (23%; responsive vs refractory ascites P.001; recurrent vs refractory ascites P = .022).In an analysis of data from a large cohort of outpatients with cirrhosis, we found that grade 1 ascites is associated with systemic inflammation, more complications, and increased mortality compared with no ascites. Mortality does not differ significantly between patients with recurrent ascites vs ascites responsive to medical treatment.

Backgound: This study was aimed at evaluating the presepsin and procalcitonin levels to predict adverse postoperative complications and mortality in cardiac surgery patients. Methods: A total of 122 cardiac surgery patients were enrolled for the study. Presepsin and procalcitonin levels were measured 48 h after the procedure. The primary endpoints were adverse renal, respiratory, and cardiovascular outcomes and mortality. Results: Presepsin and procalcitonin levels were significantly higher in patients with adverse renal and respiratory outcome (p < 0.001 and 0.0081). The presepsin levels were significantly higher in patients with adverse cardiovascular outcome (p = 0.023) and the procalcitonin values in patients with sepsis (p = 0.0013). Presepsin levels were significantly higher in patients who died during hospitalization (382 pg/mL, interquartile range [IQR] 243–717.5 vs. 1,848 pg/mL, IQR 998–5,451.5, p = 0.049). In addition, the predictive value for in-hospital, 30-days, and 6-months mortality was higher for presepsin, with a significant difference between the 2 biomarkers (p = 0.025, p = 0.035, p = 0.003; respectively). Presepsin and procalcitonin seem to have comparable predictive value for adverse renal, cardiovascular, and respiratory outcome in cardiac surgery patients. Although a positive trend was notable for presepsin and adverse renal outcome (area under the ROC [receiver operating characteristic] curves [AUC] of 0.760, 95% CI 0.673–0.833 versus procalcitonin: AUC 0.692; 95% CI 0.601–0.773): no statistically significant difference was evident between the AUC of the 2 biomarkers (p = 0.25). Conclusions: Presepsin and ­procalcitonin seem to have comparable predictive value for ­adverse renal, cardiovascular, and respiratory outcome in cardiac surgery patients. Also, presepsin possesses a better predictive value for in-hospital, 30-days, and 6-months mortality.

Background: Cardiac surgery is a leading cause of acute kidney injury (AKI). Such AKI patients may develop progressive chronic kidney disease (CKD). Others, who appear to have sustained no permanent loss of function (normal serum creatinine), may still lose renal functional reserve (RFR). Methods: We extended the follow-up in the observational 'Preoperative RFR Predicts Risk of AKI after Cardiac Surgery' study from hospital discharge to 3 months after surgery for 86 (78.2%) patients with normal baseline estimated glomerular filtration rate (eGFR), and re-measured RFR with a high oral protein load. The primary study endpoint was change in RFR. Study registration at clinicaltrials.gov Identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759. Results: At 3 months, three patients developed new CKD. All remaining patients continued to have a normal eGFR (93.3 ± 15.1 mL/min/1.73 m2). However, when stratified by post-operative AKI and cell cycle arrest (CCA) biomarkers, AKI patients displayed a significant decrease in RFR {from 14.4 [interquartile range (IQR) 9.5 - 24.3] to 9.1 (IQR 7.1 - 12.5) mL/min/1.73 m2; P

Cardiorenal syndrome type 4 (CRS-4) has been defined as “chronic abnormalities in renal function leading to cardiac disease” and recognizes the extreme burden of cardiovascular risk in patients with chronic kidney disease (CKD). CKD is common and increasingly recognized as a risk factor for cardiovascular disease. Even though the treatment for cardiovascular disease has improved dramatically over the past decades, it still is responsible for up to 50% of deaths in CKD patients. Patients with CKD have not only traditional cardiovascular risk factors, such as hypertension, dyslipidemia, and left ventricular hypertrophy, but also nonconventional cardiovascular risk factors, such as anemia, calcium, and phosphorus abnormalities and posttranslational modifications. For this reason, patients with CKD should be evaluated thoroughly for cardiovascular risk factors that require a careful management. A high index of suspicion for cardiovascular morbidity, proper diagnosis, aggressive risk management, and intervention is essential to provide a better survival for patients with CKD.

Background: Cardiorenal syndrome type 1 (CRS type 1) is characterized by a rapid worsening of cardiac function leading to acute kidney injury (AKI). Inflammation and oxidative stress seem to play a pivotal role in its pathophysiology. In this in vivo study, we examined the putative role of inflammation and humoral markers in the pathogenesis of the CRS type 1. Methods: We enrolled 53 patients with acute heart failure (AHF); 17 of them developed AKI (CRS type 1). The cause of AKI was presumed to be related to cardiac dysfunction after having excluded other causes. We assessed the plasma levels of proinflammatory cytokines (TNF-α, IL-6, IL-18, sICAM, RANTES, GMCSF), oxidative stress marker (myeloperoxidase, MPO), brain natriuretic peptide (BNP), and neutrophil gelatinase-associated lipocalin (NGAL) in AHF and CRS type 1 patients. Results: We observed a significant increase in IL-6, IL-18, and MPO levels in CRS type 1 group compared to AHF (p < 0.001). We found higher NGAL at admission in the CRS type 1 group compared to the AHF group (p = 0.008) and a positive correlation between NGAL and IL-6 (Spearman’s rho = 0.45, p = 0.003) and between IL-6 and BNP (Spearman’s rho = 0.43, p = 0.004). We observed lower hemoglobin levels in CRS type 1 patients compared to AHF patients (p < 0.05) and inverse correlation between hemoglobin and cytokines (IL-6: Spearman’s rho = –0.38, p = 0.005; IL-18: Spearman’s rho = –0.32, p = 0.02). Conclusion: Patients affected by CRS type 1 present increased levels of proinflammatory cytokines and oxidative stress markers, increased levels of tissue damage markers, and lower hemoglobin levels. All these factors may be implicated in the pathophysiology of CRS type 1 syndrome.

Cardiorenal syndrome type 5 (CRS-5) includes conditions where there is a simultaneous involvement of the heart and kidney from a systemic disorder. This is a bilateral organ cross talk. Fabry's disease (FD) is a devastating progressive inborn error of metabolism with lysosomal glycosphingolipid deposition in variety of cell types, capillary endothelial cells, renal, cardiac and nerve cells. Basic effect is absent or deficient activity of lysosomal exoglycohydrolase a-galactosidase A. Renal involvement consists of proteinuria, isosthenuria, altered tubular function, presenting in second or third decade leading to azotemia and end-stage renal disease in third to fifth decade mainly due to irreversible changes to glomerular, tubular and vascular structures, especially highlighted by podocytes foot process effacement. Cardiac involvement consists of left ventricular hypertrophy, right ventricular hypertrophy, arrhythmias (sinus node and conduction system impairment), diastolic dysfunction, myocardial ischemia, infarction, transmural replacement fibrosis, congestive heart failure and cardiac death. Management of FD is based on enzymatic replacement therapy and control of renal (with anti-proteinuric agents such as angiotensin-converting enzyme inhibitors-and/or angiotensin II receptor blockers), brain (coated aspirin, clopidogrel and statin to prevent strokes) and heart complications (calcium channel blockers for ischemic cardiomyopathy, warfarin and amiodarone or cardioverter device for arrhythmias).

Over the past decade, science has greatly advanced our understanding of interdependent feedback mechanisms involving the heart, lung, and kidney. Organ injury is the consequence of maladaptive neurohormonal activation, oxidative stress, abnormal immune cell signaling, and a host of other mechanisms that precipitate adverse functional and structural changes. The presentation of interorgan crosstalk may include an acute, chronic, or acute on chronic timeframe. We review the current, state-of-the-art understanding of cardio-pulmonary-renal interactions and their related pathophysiology, perpetuating nature, and cycles of increased susceptibility and reciprocal progression. To this end, we present a multidisciplinary approach to frame the diverse spectrum of published observations on the topic. Assessment of organ functional reserve and use of biomarkers are valuable clinical strategies to screen and detect disease, assist in diagnosis, assess prognosis, and predict recovery or progression to chronic disease.

In this study, we examined the possible immune-mediated mechanisms in cardiorenal syndrome (CRS) type 1 pathogenesis. We enrolled 40 patients with acute heart failure (AHF), 11 patients with CRS type 1 and 15 controls. Plasma from the different groups was incubated with monocytes; subsequently, cell apoptosis was evaluated by DNA fragmentation, caspase activity and cytofluorometric assay. Cytokine quantification in plasma and supernatant was performed by ELISA. Monocytes treated with CRS type 1 plasma showed significantly higher apoptosis compared with those treated with AHF and the controls (p < 0.05). Caspase-3 (CRS type 1: 2.20 ng/ml, IQR 2.06-2.33; AHF: 1.48 ng/ml, IQR 1.31-1.56; controls: 0.71 ng/ml, IQR 0.67-0.81) and caspase-8 levels (CRS type 1: 1.49 ng/ml, IQR 1.42-1.57; AHF: 0.94 ng/ml, IQR 0.84-0.98; controls: 0.56 ng/ml, IQR 0.51-0.58) in cells incubated with plasma from these patients demonstrated a significantly higher concentration. We observed a strong upregulation of plasma IL-6 and IL-18 in CRS type 1 compared with AHF and the controls (p < 0.05). Interestingly, we observed a similar concentration of TNF-α in CRS type 1 and AHF. In CRS type 1 patients, IL-6 (52.13 ng/ml, IQR 47.29-66.83) and IL-18 levels (197.75 ng/ml, IQR 120.80-265.49) in supernatant were significantly higher than in AHF patients (IL-6: 28.79 ng/ml, IQR 19.90-36.10; IL-18: 21.98 ng/ml, IQR 15.98-29.85) and controls (IL-6: 5.02 ng/ml, IQR 4.56-6.44; IL-18: 7.91 ng/ml, IQR 5.57-10.62). These findings suggest the presence of a defective regulation of monocyte apoptosis in CRS type 1 patients and the involvement of an immune-mediated mechanism in the pathophysiology of this syndrome.

Cardiorenal syndrome (CRS) type 3 is a subclassification of the CRS whereby an episode of acute kidney injury (AKI) leads to the development of acute cardiac injury or dysfunction. In general, there is limited understanding of the pathophysiologic mechanisms involved in CRS type 3. An episode of AKI may have effects that depend on the severity and duration of AKI and that both directly and indirectly predispose to an acute cardiac event. Experimental data suggest that cardiac dysfunction may be related to immune system activation, inflammatory mediators release, oxidative stress, and cellular apoptosis which are well documented in the setting of AKI. Moreover, significant derangements, such as fluid and electrolyte imbalance, metabolic acidosis, and uremia, which are typical features of acute kidney injury, may impair cardiac function. In this review, we will focus on multiple factors possibly involved in the pathogenesis issues regarding CRS type 3.

Patients with cirrhosis have a high risk of bacterial infections. Bacterial infections induce systemic inflammation that may lead to organ failure and acute-on-chronic liver failure (ACLF) resulting in a high risk of short term mortality. The early diagnosis and treatment of bacterial infections is essential to improve the patient's prognosis. However, in recent years, the spread of multidrug resistant (MDR) bacterial infections has reduced the efficacy of commonly used antibiotics such as third generation cephalosporins. In patients at high risk of MDR bacteria, such as those with nosocomial infections, the early administration of broad spectrum antibiotics has been shown to improve the prognosis. However, early de-escalation of antibiotics is recommended to reduce a further increase in antibiotic resistance. Strategies to prevent acute kidney injury and other organ failures should be implemented. Although prophylaxis of bacterial infections with antibiotics improves the prognosis in selected patients, their use should be limited to patients at high risk of developing infections. In this article, we review the pathogenesis and management of bacterial infections in patients with cirrhosis.

Although acute kidney injury (AKI) frequently complicates cardiac operations, methods to determine AKI risk in patients without underlying kidney disease are lacking. Renal functional reserve (RFR) can be used to measure the capacity of the kidney to increase glomerular filtration rate under conditions of physiologic stress and may serve as a functional marker that assesses susceptibility to injury. We sought to determine whether preoperative RFR predicts postoperative AKI.We enrolled 110 patients with normal resting glomerular filtration rates undergoing elective cardiac operation. Preoperative RFR was measured by using a high oral protein load test. The primary end point was the ability of preoperative RFR to predict AKI within 7 days of operation. Secondary end points included the ability of a risk prediction model, including demographic and comorbidity covariates, RFR, and intraoperative variables to predict AKI, and the ability of postoperative cell cycle arrest markers at various times to predict AKI.AKI occurred in 15 patients (13.6%). Preoperative RFR was lower in patients who experienced AKI (p 0.001) and predicted AKI with an area under the receiver operating characteristic curve (AUC) of 0.83 (95% confidence interval [CI]: 0.70 to 0.96). Patients with preoperative RFRs not greater than 15 mL · minAmong elective cardiac surgical patients with normal resting glomerular filtration rates, preoperative RFR was highly predictive of AKI. A reduced RFR appears to be a novel risk factor for AKI, and measurement of RFR preoperatively can identify patients who are likely to benefit from preventive measures or to select for use of biomarkers for early detection. Larger prospective studies to validate the use of RFR in strategies to prevent AKI are warranted. ClinicalTrials.gov identifier: NCT03092947, ISRCTN Registry: ISRCTN16109759.

Background The renal assist device (RAD) is a blood purification system containing viable renal tubular epithelial cells (TECs) that has been proposed for the treatment of acute kidney injury (AKI) and multiple organ failure. Perfluorocarbons (PFCs) are oxygen carriers used for organ preservation in transplantation. The aim of this study was to investigate the effect of PFCs on hypoxia- and sepsis-induced TEC injury and on renal CD133+ progenitor differentiation in a microenvironment similar to the RAD. Methods TECs were seeded in a polysulphone hollow fibre under hypoxia or cultured with plasma from 10 patients with sepsis-associated AKI in the presence or absence of PFCs and were tested for cytotoxicity (XTT assay), apoptosis (terminal deoxynucleotidyl transferase dUTP nick end labeling assay, caspases, enzyme-linked immunosorbent assay, Fas/Fas Ligand pathway activation), mitochondrial activity, cell polarity [transepithelial electrical resistance (TEER)] and adenosine triphosphate production. The effect of PFCs on proliferation and differentiation of human CD133+ progenitors was also studied. Results In the presence of PFCs, TECs seeded into the polysulphone hollow fibre showed increased viability and expression of insulin-like growth factor 1, hepatocyte growth factor and macrophage-stimulating protein. Plasma from septic patients induced TEC apoptosis, disruption of oxidative metabolism, alteration of cell polarity and albumin uptake, down-regulation of the tight junction protein ZO-1 and the endocytic receptor megalin on the TEC surface. These detrimental effects were significantly reduced by PFCs. Moreover, PFCs induced CD133+ renal progenitor cell proliferation and differentiation towards an epithelial/tubular-like phenotype. Conclusions PFCs improved the viability and metabolic function of TECs seeded within a polysulphone hollow fibre and subjected to plasma from septic AKI patients. Additionally, PFCs promoted differentiation towards a tubular/epithelial phenotype of CD133+ renal progenitor cells.

IntroductionPatients with cirrhosis have a high risk of sepsis, which confers a poor prognosis. The systemic inflammatory response syndrome (SIRS) criteria have several limitations in cirrhosis. Recently, new criteria for sepsis (Sepsis-3) have been suggested in the general population (increase of Sequential Organ Failure Assessment (SOFA) ≥2 points from baseline). Outside the intensive care unit (ICU), the quick SOFA (qSOFA (at least two among alteration in mental status, systolic blood pressure ≤100 mm Hg or respiratory rate ≥22/min)) was suggested to screen for sepsis. These criteria have never been evaluated in patients with cirrhosis. The aim of the study was to assess the ability of Sepsis-3 criteria in predicting in-hospital mortality in patients with cirrhosis and bacterial/fungal infections.Methods259 consecutive patients with cirrhosis and bacterial/fungal infections were prospectively included. Demographic, laboratory and microbiological data were collected at diagnosis of infection. Baseline SOFA was assessed using preadmission data. Patients were followed up until death, liver transplantation or discharge. Findings were externally validated (197 patients).ResultsSepsis-3 and qSOFA had significantly greater discrimination for in-hospital mortality (area under the receiver operating characteristic (AUROC)=0.784 and 0.732, respectively) than SIRS (AUROC=0.606) (pConclusionsSepsis-3 criteria are more accurate than SIRS criteria in predicting the severity of infections in patients with cirrhosis. qSOFA is a useful bedside tool to assess risk for worse outcomes in these patients. Patients with Sepsis-3 and positive qSOFA deserve more intensive management and strict surveillance.

Epigenetics is defined as the heritable changes in gene expression patterns which are not directly encoded by modifications in the nucleotide DNA sequence of the genome, including higher order chromatin organization, DNA methylation, cytosine modifications, covalent histone tail modifications, and short non-coding RNA molecules. Recently, much attention has been paid to the role and the function of epigenetics and epimutations in the cellular and subcellular pathways and in the regulation of genes in the setting of both kidney and cardiovascular disease. Indeed, deregulation of histone alterations has been highlighted in a large spectrum of renal and cardiac disease, including chronic and acute renal injury, renal and cardiac fibrosis, cardiac hypertrophy and failure, kidney congenital anomalies, renal hypoxia, and diabetic renal complications. Nevertheless, the role of epigenetics in the pathogenesis and pathophysiology of cardiorenal syndromes is currently underexplored. Given the significant clinical relevance of heart-kidney crosstalk, efforts in the research for new action mechanisms concurrently operating in both pathologies are thus of maximum interest. This review focuses on epigenetic mechanisms involved in heart and kidney disease, and their possible role in the setting of cardiorenal syndromes.