Kidney Fibrosis and Oxidative Stress: From Molecular Pathways to New Pharmacological Opportunities.

Kidney fibrosis, diffused into the interstitium, vessels, and glomerulus, is the main pathologic feature associated with loss of renal function and chronic kidney disease (CKD). Fibrosis may be triggered in kidney diseases by different genetic and molecular insults. However, several studies have shown that fibrosis can be linked to oxidative stress and mitochondrial dysfunction in CKD. In this review, we will focus on three pathways that link oxidative stress and kidney fibrosis, namely: (i) hyperglycemia and mitochondrial energy imbalance, (ii) the mineralocorticoid signaling pathway, and (iii) the hypoxia-inducible factor (HIF) pathway. We selected these pathways because they are targeted by available medications capable of reducing kidney fibrosis, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1alpha-prolyl hydroxylase inhibitors. These drugs have shown a reduction in oxidative stress in the kidney and a reduced collagen deposition across different CKD subtypes. However, there is still a long and winding road to a clear understanding of the anti-fibrotic effects of these compounds in humans, due to the inherent practical and ethical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers measurable in easily accessible matrices like urine. In this narrative review, we will describe these three pathways, their interconnections, and their link to and activity in oxidative stress and kidney fibrosis.

A Role of Circuit Clotting and Strategies to Prevent It during Blood Purification Therapy with oXiris Membrane: An Observational Multicenter Study.

INTRODUCTION: Membrane fouling is a significant complication potentially reducing clinical effects of extracorporeal blood purification (EBP) in critically ill septic patients with acute kidney injury. Although fascinating, the effect of heparin coating in preventing membrane fouling is currently unknown. This multicenter prospective study aims to preliminary describe the incidence, associated factors, and clinical consequences of premature circuit clotting in a cohort of adult critically ill septic patients treated with EBP using a high biocompatible heparin-coated hemodiafilter characterized by advanced adsorption properties. METHODS: This study was a retrospective analysis of prospectively entered data in the oXirisNet Registry; overall, 97 septic patients undergoing EBP with oXiris between May 2019 and March 2020 were enrolled in this study. Patients were divided into two groups according to the occurrence of filter clotting (premature vs. nonpremature). Logistic regression analysis was used to identify factors associated with premature circuit clotting. RESULTS: Premature clotting occurred in 18 (18.6%) patients. Results of the multivariate logistic regression analysis demonstrated that hematocrit (p = 0.02, odds ratio [OR] 1.15 [1.05; 1.30]), serum procalcitonin (PCT) (p = 0.03, OR 1.1 [1.05; 1.2]), and anticoagulation strategy (p = 0.05 at Wald's test) were independent predictors of circuit clotting. Systemic anticoagulation (p = 0.02, OR 0.03 [0.01; 0.52]) and regional citrate anticoagulation (p = 0.10, OR 0.23 [0.04; 1.50]) were both protective factors if compared to no-anticoagulation strategy. Patients with nonpremature circuit clotting showed more rapid recovery from hemodynamic instability, pulmonary hypo-oxygenation, and electrolyte disorders and greater improvement of inflammatory markers and SOFA scores. CONCLUSION: Although in this study the incidence of premature circuit clotting was relatively low (18.6%) compared to previously reported values (54%), membrane clotting in adult critically ill septic patients could cause clinically relevant interferences with treatment performances. Prevention of clotting should be based on avoiding higher patients' hematocrit, high serum PCT, and no-anticoagulation strategy which resulted as independent predictors of circuit clotting.

Blood purification therapy with a hemodiafilter featuring enhanced adsorptive properties for cytokine removal in patients presenting COVID-19: a pilot study.

BACKGROUND: Systemic inflammation in COVID-19 often leads to multiple organ failure, including acute kidney injury (AKI). Renal replacement therapy (RRT) in combination with sequential extracorporeal blood purification therapies (EBP) might support renal function, attenuate systemic inflammation, and prevent or mitigate multiple organ dysfunctions in COVID-19. AIM: Describe overtime variations of clinical and biochemical features of critically ill patients with COVID-19 treated with EBP with a hemodiafilter characterized by enhanced cytokine adsorption properties. METHODS: An observational prospective study assessing the outcome of patients with COVID-19 admitted to the ICU (February to April 2020) treated with EBP according to local practice. Main endpoints included overtime variation of IL-6 and multiorgan function-scores, mortality, and occurrence of technical complications or adverse events. RESULTS: The study evaluated 37 patients. Median baseline IL-6 was 1230 pg/ml (IQR 895) and decreased overtime (p < 0.001 Kruskal-Wallis test) during the first 72 h of the treatment, with the most significant decrease in the first 24 h (p = 0.001). The reduction in serum IL-6 concentrations correlated with the improvement in organ function, as measured in the decrease of SOFA score (rho = 0.48, p = 0.0003). Median baseline SOFA was 13 (IQR 6) and decreased significantly overtime (p < 0.001 at Kruskal-Wallis test) during the first 72 h of the treatment, with the most significant decrease in the first 48 h (median 8 IQR 5, p = 0.001). Compared to the expected mortality rates, as calculated by APACHE IV, the mean observed rates were 8.3% lower after treatment. The best improvement in mortality rate was observed in patients receiving EBP early on during the ICU stay. Premature clotting (running < 24 h) occurred in patients (18.9% of total) which featured higher effluent dose (median 33.6 ml/kg/h, IQR 9) and higher filtration fraction (median 31%, IQR 7.4). No electrolyte disorders, catheter displacement, circuit disconnection, unexpected bleeding, air, or thromboembolisms due to venous cannulation of EBP were recorded during the treatment. In one case, infection of vascular access occurred during RRT, requiring replacement. CONCLUSIONS: EBP with heparin-coated hemodiafilter featuring cytokine adsorption properties administered to patients with COVID-19 showed to be feasible and with no adverse events. During the treatment, patients experienced serum IL-6 level reduction, attenuation of systemic inflammation, multiorgan dysfunction improvement, and reduction in expected ICU mortality rate.

[Acute Kidney Injury: the nephrology plus value and competence and a good organization can ameliorate the prognosis]. / Insufficienza Renale Acuta: il plus valore e la competenza del nefrologo, unitamente ad una buona organizzazione, possono migliorare la prognosi.

Epidemiology of Acute Kidney Injury (AKI) has changed radically in the past 15 years: we have observed an exponential increase of cases with high mortality and residual disability, particularly in those patients who need dialysis treatment. Those who survive AKI have an increased risk of requiring dialysis after hospital discharge over the short term as well as long term. They have an increased risk of deteriorating residual kidney function and cardiovascular events as well as a shorter life expectancy. Given the severe prognosis, difficulties of treatment, high level of resources needed, increased workload and consequently costs, several aspects of AKI have not been sufficiently investigated. Any national register of AKI has not been developed and its absence has an impact on provisional strategies. Specific training should be planned beginning with University, which should include practical training in Intensive Care Units. A definition of the organizational characteristics and requirements for the care of AKI is needed. Treatment of AKI is not based exclusively on dialysis efficiency or technology, but also on professional skills, volume of activity, clinical experience, model of healthcare organizations, continuity of processes and medical activities to guarantee such as a closed-staff system. Progress in knowledge and technology has only partially modified the outcome and prognosis of AKI patients; consequently, new strategies based on increased awareness, on the implementation of professional skills, and on revision, definition and updating of resources for the organization of AKI management are needed and expected over the short term.

Outcome in noncritically ill patients with acute kidney injury requiring dialysis: Effects of differing medical staffs and organizations.

Acute kidney injury requiring dialysis (AKI-D) treatment has significantly increased in incidence over the years, with more than 400 new cases per million population/y, 2/3 of which concern noncritically ill patients. In these patients, there are little data on mortality or on information of care organization and its impact on outcome. Specialty training and integrated teams, as well as a high volume of activity, seem to be linked to better hospital outcome. The study investigates mortality of patients admitted to and in-care of nephrology (NEPHROpts), a closed-staff organization, and to other medical wards (MEDpts), representing a model of open-staff organization.This is a single center, case-control cohort study derived from a prospective epidemiology investigation on patients with AKI-D admitted to or in-care of the Hospital of Perugia during the period 2007 to 2014. Noncritically ill AKI-D patients were analyzed: inclusion and exclusion criteria were defined to avoid possible bias on the cause of hospital admittance and comorbidities, and a propensity score (PS) matching was performed.Six hundred fifty-four noncritically ill patients were observed and 296 fulfilled inclusion/exclusion criteria. PS matching resulted in 2 groups: 100 NEPHROpts and 100 MEDpts. Characteristics, comorbidities, acute kidney injury causes, risk-injury-failure acute kidney injury criteria, and simplified acute physiology score (SAPS 2) were similar. Mortality was 36%, and a difference was reported between NEPHROpts and MEDpts (20% vs 52%, χ = 23.2, P < 0.001). Patients who died differed in age, serum creatinine, blood urea nitrogen/s.Creatinine ratio, dialysis urea reduction rate (URR), SAPS 2 and Charlson score; they presented a higher rate of heart disease, and a larger proportion required noradrenaline/dopamine for shock. After correction for mortality risk factors, multivariate Cox analysis revealed that site of treatment (medical vs nephrology wards) represents an independent risk factor of mortality (relative risk = 2.13, 95% confidence interval = 1.25, 3.63; P < 0.01). Other independent risk factors were age, URR, s.Creatinine at hemodialysis beginning, and SAPS 2 score.In our context, we have documented that noncritically ill AKI-D patients, who represented 2/3 of the population, had high in-hospital mortality (36%), and that a closed-staff specialty medical organization, such as a Nephrology team, seems to guarantee a better outcome than general medical organizations. The significance in healthcare system organization and resource allocation could be important.

Six-year single-center survey on AKI requiring renal replacement therapy: epidemiology and health care organization aspects.

Evidence regarding hospital-based acute kidney injury (AKI) reveals a continuous increase in incidence over the years, at least in intensive care units (ICU). Fewer reports are available for non critically-ill patients admitted to general or specialist wards other than ICU (non-ICU). The consequence of greater incidence is an increase in therapies such as dialysis; but how the health care organization deals with this problem is not clearly known. Here we quantified the incidence of dialysis-requiring AKI (AKI-D) among patients admitted to a University Hospital which serves a population of 354,000 inhabitants. Between 2007 and 2012, the incidence of AKI-D increased from 209 to 410 per million population (pmp)/year; age of patients and cardiovascular comorbid pathologies also increased. AKI-D was more frequent in non-ICU and 32% of patients were admitted to ICU. Considering the site of treatment of non-ICU patients, in 2007 the ratio of patients admitted to non-ICU wards apart from Nephrology to those admitted to Nephrology was 1:1, but in 2012 the ratio increased to 2.4:1 (p < 0.05). The complexity of acute disease, measured with the New Simplified Acute Physiology Score (SAPS II), did not reveal differences over the years. The number of dialysis treatments/year increased by 82%, and the total hours/year increased by 86%. Low-efficiency daily dialysis was performed in 52.4% of patients admitted to ICU, but dialysis sessions longer than 8 h were performed in only 40% of cases. Overall, 6-year mortality was 48.8%, without significant differences over the years. Mortality in ICU was 65.6%, and in non-ICU 41.2% (p < 0.001). Dialysis treatments needed to be continued after hospital discharge in 21% of patients. We conclude that dialysis-requiring AKI is becoming more common, and that two-thirds of patients are admitted as non-ICU: in these patients, during the last year of the study, the treatment site was more frequently in non-ICUs other than Nephrology. Over the 6-year period, the local healthcare organization had to dispense 80% more dialysis treatments/year in terms of total number and hours of treatment. One-fifth of surviving patients needed to continue dialysis after hospital discharge. Our data highlight the public health importance of AKI and the need for adequate resources for Nephrology.