Contrast-Induced Acute Kidney Injury in Patients with Heart Failure on Sodium-Glucose Cotransporter-2 Inhibitors Undergoing Radiocontrast Agent Invasive Procedures: A Propensity-Matched Analysis.

(1) Background: This single-center retrospective study aimed to evaluate whether sodium-glucose cotransporter-2 inhibitors (SGLT2-i) therapy may have a nephroprotective effect to prevent contrast-induced acute kidney injury (CI-AKI) in patients with heart failure (HF) undergoing iodinated contrast medium (ICM) invasive procedures. (2) Methods: The population was stratified into SGLT2-i users and SGLT2-i non-users according to the chronic treatment with gliflozins. The primary endpoint was CI-AKI incidence during hospitalization. Secondary endpoints were all-cause mortality and the need for continuous renal replacement therapy (CRRT). (3) Results: In total, 86 patients on SGLT2-i and 179 patients not on SGLT2-i were enrolled. The incidence of CI-AKI in the gliflozin group was lower than in the non-user group (9.3 vs. 27.3%, p < 0.001), and these results were confirmed after propensity matching analysis. Multivariable logistic regression showed that only SGLT2-i treatment was an independent preventive factor for CI-AKI (OR: 0.41, 95% CI: 0.16-0.90, p = 0.045). The need for CRRT was reported only in five patients in the non-SGLT2-i-user group compared to zero patients in the gliflozin group (p = 0.05). (4) Conclusions: SGLT2-i therapy was associated with a lower risk of CI-AKI in patients with HF undergoing ICM invasive procedures.

B-Cell Activation Biomarkers in Salivary Glands Are Related to Lymphomagenesis in Primary Sjögren's Disease: A Pilot Monocentric Exploratory Study.

Primary Sjögren's disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin's lymphoma (NHL). Over the last few decades, microRNA-155 (miR-155) has arisen as a key regulator of B-cells. Nevertheless, its role in primary Sjögren's disease remains elusive. Thus, the purpose of this study was (i) to explore miR-155, B-cell activating factor (BAFF)-receptor (BAFF-R), and Interleukin 6 receptor (IL-6R) expression in the labial salivary glands (LSG) of patients with primary Sjögren's disease, aiming to identify potential B-cell activation biomarkers related to NHL development. Twenty-four patients with primary Sjögren's disease, and with available tissue blocks from a LSG biopsy performed at diagnosis, were enrolled. Among them, five patients developed B-cell NHL during follow-up (7.3 ± 3.1 years). A comparison group of 20 individuals with sicca disease was included. Clinical and laboratory parameters were recorded and the LSG biopsies were evaluated to assess local inflammation in terms of miR-155/BAFF-R and IL-6R expression. Stratifying the primary Sjögren's disease cohort according to lymphomagenesis, miR-155 was upregulated in primary Sjögren's disease patients who experienced NHL, more so than those who did not experience NHL. Moreover, miR-155 expression correlated with the focus score (FS), as well as BAFF-R and IL-6R expression, which were increased in primary Sjögren's disease patients and in turn related to neoplastic evolution. In conclusion, epigenetic modulation may play a crucial role in the aberrant activation of B-cells in primary Sjögren's disease, profoundly impacting the risk of NHL development.

A Clinical Workflow for Cost-Saving High-Rate Diagnosis of Genetic Kidney Diseases.

SIGNIFICANCE STATEMENT: To optimize the diagnosis of genetic kidney disorders in a cost-effective manner, we developed a workflow based on referral criteria for in-person evaluation at a tertiary center, whole-exome sequencing, reverse phenotyping, and multidisciplinary board analysis. This workflow reached a diagnostic rate of 67%, with 48% confirming and 19% modifying the suspected clinical diagnosis. We obtained a genetic diagnosis in 64% of children and 70% of adults. A modeled cost analysis demonstrated that early genetic testing saves 20% of costs per patient. Real cost analysis on a representative sample of 66 patients demonstrated an actual cost reduction of 41%. This workflow demonstrates feasibility, performance, and economic effect for the diagnosis of genetic kidney diseases in a real-world setting. BACKGROUND: Whole-exome sequencing (WES) increases the diagnostic rate of genetic kidney disorders, but accessibility, interpretation of results, and costs limit use in daily practice. METHODS: Univariable analysis of a historical cohort of 392 patients who underwent WES for kidney diseases showed that resistance to treatments, familial history of kidney disease, extrarenal involvement, congenital abnormalities of the kidney and urinary tract and CKD stage ≥G2, two or more cysts per kidney on ultrasound, persistent hyperechoic kidneys or nephrocalcinosis on ultrasound, and persistent metabolic abnormalities were most predictive for genetic diagnosis. We prospectively applied these criteria to select patients in a network of nephrology centers, followed by centralized genetic diagnosis by WES, reverse phenotyping, and multidisciplinary board discussion. RESULTS: We applied this multistep workflow to 476 patients with eight clinical categories (podocytopathies, collagenopathies, CKD of unknown origin, tubulopathies, ciliopathies, congenital anomalies of the kidney and urinary tract, syndromic CKD, metabolic kidney disorders), obtaining genetic diagnosis for 319 of 476 patients (67.0%) (95% in 21 patients with disease onset during the fetal period or at birth, 64% in 298 pediatric patients, and 70% in 156 adult patients). The suspected clinical diagnosis was confirmed in 48% of the 476 patients and modified in 19%. A modeled cost analysis showed that application of this workflow saved 20% of costs per patient when performed at the beginning of the diagnostic process. Real cost analysis of 66 patients randomly selected from all categories showed actual cost reduction of 41%. CONCLUSIONS: A diagnostic workflow for genetic kidney diseases that includes WES is cost-saving, especially if implemented early, and is feasible in a real-world setting.

Pre-Dialysis B-Line Quantification at Lung Ultrasound Is a Useful Method for Evaluating the Dry Weight and Predicting the Risk of Intradialytic Hypotension.

Intradialytic hypotension (IDH) is a frequent and well-known complication of hemodialysis, occurring in about one third of patients. An integrated approach with different methods is needed to minimize IDH episodes and their complications. In this prospective observational study, recruited patients underwent a multiparametric evaluation of fluid status through a lung ultrasound (LUS) with the quantification of B-lines, a physical examination, blood pressure, NT-proBNP and chest X-rays. The evaluation took place immediately before and at the end of the dialysis session, and the patients were divided into IDH and no-IDH groups. We recruited a total of 107 patients. A pre-dialysis B-line number ≥ 15 showed a high sensitivity in fluid overload diagnosis (94.5%), even higher than a chest X-ray (78%) or physical examination (72%) alone. The identification at the beginning of dialysis of <8 B-lines in the overall cohort or <20 B-lines in patients with NYHA 3−4 class are optimal thresholds for identifying those patients at higher risk of experiencing an IDH episode. In the multivariable analysis, the NYHA class, a low pre-dialysis systolic BP and a low pre-dialysis B-line number were independent risk factors for IDH. At the beginning of dialysis, the B-line quantification at LUS is a valuable and reliable method for evaluating fluid status and predicting IDH episodes. A post-dialysis B-line number <5 may allow for an understanding of whether the IDH episode was caused by dehydration, probably due to due to an overestimation of the dry weight.

Defining diagnostic trajectories in patients with podocytopathies.

Podocytopathies are glomerular disorders in which podocyte injury drives proteinuria and progressive kidney disease. They encompass a broad spectrum of aetiologies, resulting in pathological pictures of minimal-changes, focal segmental glomerulosclerosis, diffuse mesangial sclerosis or collapsing glomerulopathy. Despite improvement in classifying podocytopathies as a distinct group of disorders, the histological definition fails to capture the relevant biological heterogeneity underlying each case, manifesting as extensive variability in disease progression and response to therapies. Increasing evidence suggests that podocytopathies can result from a single causative factor or a combination of multiple genetic and/or environmental risk factors with different relative contributions, identifying complex physiopathological mechanisms. Consequently, the diagnosis can still be challenging. In recent years, significant advances in genetic, microscopy and biological techniques revolutionized our understanding of the molecular mechanisms underlying podocytopathies, pushing nephrologists to integrate innovative information with more conventional data obtained from kidney biopsy in the diagnostic workflow. In this review, we will summarize current approaches in the diagnosis of podocytopathies, focusing on strategies aimed at elucidating the aetiology underlying the histological picture. We will provide several examples of an integrative view of traditional concepts and new data in patients with suspected podocytopathies, along with a perspective on how a reclassification could help to improve not only diagnostic pathways and therapeutic strategies, but also the management of disease recurrence after kidney transplantation. In the future, the advantages of precision medicine will probably allow diagnostic trajectories to be increasingly focused, maximizing therapeutic results and long-term prognosis.

Differentiation of crescent-forming kidney progenitor cells into podocytes attenuates severe glomerulonephritis in mice.

Crescentic glomerulonephritis is characterized by vascular necrosis and parietal epithelial cell hyperplasia in the space surrounding the glomerulus, resulting in the formation of crescents. Little is known about the molecular mechanisms driving this process. Inducing crescentic glomerulonephritis in two Pax2Cre reporter mouse models revealed that crescents derive from clonal expansion of single immature parietal epithelial cells. Preemptive and delayed histone deacetylase inhibition with panobinostat, a drug used to treat hematopoietic stem cell disorders, attenuated crescentic glomerulonephritis with recovery of kidney function in the two mouse models. Three-dimensional confocal microscopy and stimulated emission depletion superresolution imaging of mouse glomeruli showed that, in addition to exerting an anti-inflammatory and immunosuppressive effect, panobinostat induced differentiation of an immature hyperplastic parietal epithelial cell subset into podocytes, thereby restoring the glomerular filtration barrier. Single-cell RNA sequencing of human renal progenitor cells in vitro identified an immature stratifin-positive cell subset and revealed that expansion of this stratifin-expressing progenitor cell subset was associated with a poor outcome in human crescentic glomerulonephritis. Treatment of human parietal epithelial cells in vitro with panobinostat attenuated stratifin expression in renal progenitor cells, reduced their proliferation, and promoted their differentiation into podocytes. These results offer mechanistic insights into the formation of glomerular crescents and demonstrate that selective targeting of renal progenitor cells can attenuate crescent formation and the deterioration of kidney function in crescentic glomerulonephritis in mice.

Molecular Mechanisms and Biomarkers Associated with Chemotherapy-Induced AKI.

Acute kidney injury (AKI) is a life-threatening condition characterized by a rapid and transient decrease in kidney function. AKI is part of an array of conditions collectively defined as acute kidney diseases (AKD). In AKD, persistent kidney damage and dysfunction lead to chronic kidney disease (CKD) over time. A variety of insults can trigger AKI; however, chemotherapy-associated nephrotoxicity is increasingly recognized as a significant side effect of chemotherapy. New biomarkers are urgently needed to identify patients at high risk of developing chemotherapy-associated nephrotoxicity and subsequent AKI. However, a lack of understanding of cellular mechanisms that trigger chemotherapy-related nephrotoxicity has hindered the identification of effective biomarkers to date. In this review, we aim to (1) describe the known and potential mechanisms related to chemotherapy-induced AKI; (2) summarize the available biomarkers for early AKI detection, and (3) raise awareness of chemotherapy-induced AKI.

The Impact of the SARS-CoV-2 Pandemic on Healthcare Provision in Italy to non-COVID Patients: a Systematic Review.

BACKGROUND: Italy has been one of the countries most affected by the SARS-CoV-2 pandemic, and the regional healthcare system has had to quickly adapt its organization to meet the needs of infected patients. This has led to a drastic change in the routine management of non-communicable diseases with a potential long-term impact on patient health care. Therefore, we investigated the management of non-COVID-19 patients across all medical specialities in Italy. METHODS: A PRISMA guideline-based systematic review of the literature was performed using PubMed, Embase, and Scopus, restricting the search to the main outbreak period in Italy (from February 20 to June 25 2020). We selected articles in English or Italian that detailed changes in the Italian hospital care for non-COVID-19 patients due to the pandemic. Our keywords included all medical specialities combined with our geographical focus (Italy) and COVID-19. RESULTS: Of the 4643 potentially eligible studies identified by the search, 247 were included. A decrease in the management of emergencies in non-COVID patients was found together with an increase in mortality. Similarly, non-deferrable conditions met a tendency toward decreased diagnosis. All specialities have been affected by the re-organization of healthcare provision in the hub-and-spoke system and have benefited from telemedicine. CONCLUSIONS: Our work highlights the changes in the Italian public healthcare system to tackle the developing health crisis due to the COVID-19 pandemic. The findings of our review may be useful to analyse future directions for the healthcare system in the case of new pandemic scenarios.

Threatening drug-drug interaction in a kidney transplant patient with coronavirus disease 2019 (COVID-19).

During the novel coronavirus pandemic, organ transplant recipients represent a frail susceptible category due to long-term immunosuppressive therapy. For this reason, clinical manifestations may differ from general population and different treatment approaches may be needed. We present the case of a 36-year-old kidney-transplanted woman affected by Senior-Loken syndrome diagnosed with COVID-19 pneumonia after a contact with her positive mother. Initial symptoms were fatigue, dry cough, and coryza; she never had fever nor oxygen supplementation. Hydroxychloroquine and lopinavir/ritonavir were started, and the antiviral drug was replaced with darunavir/cobicistat after 2 days for diarrhea. Immunosuppressant levels were closely monitored, and we observed very high tacrolimus trough levels despite initial dose reduction. The patient was left with steroid therapy alone. The peculiarity of clinical presentation and the management difficulties represent the flagship of our case report. We stress the need for guidelines in transplant recipients with COVID-19 infection with particular regard to the management of therapy.

The functional synergism of microRNA clustering provides therapeutically relevant epigenetic interference in glioblastoma.

MicroRNA deregulation is a consistent feature of glioblastoma, yet the biological effect of each single gene is generally modest, and therapeutically negligible. Here we describe a module of microRNAs, constituted by miR-124, miR-128 and miR-137, which are co-expressed during neuronal differentiation and simultaneously lost in gliomagenesis. Each one of these miRs targets several transcriptional regulators, including the oncogenic chromatin repressors EZH2, BMI1 and LSD1, which are functionally interdependent and involved in glioblastoma recurrence after therapeutic chemoradiation. Synchronizing the expression of these three microRNAs in a gene therapy approach displays significant anticancer synergism, abrogates this epigenetic-mediated, multi-protein tumor survival mechanism and results in a 5-fold increase in survival when combined with chemotherapy in murine glioblastoma models. These transgenic microRNA clusters display intercellular propagation in vivo, via extracellular vesicles, extending their biological effect throughout the whole tumor. Our results support the rationale and feasibility of combinatorial microRNA strategies for anticancer therapies.