Context Postoperative acute kidney injury (AKI) is a serious complication after kidney surgery, associated with prolonged hospital stay, high morbidity, and mortality. Biomarkers represent a tool of increasing importance to identify renal impairment after partial nephrectomy (PN) or radical nephrectomy (RN) in order to optimize and anticipate the diagnosis of AKI. Objective The goal of this systematic review is to investigate current insights on the role of biomarkers in predicting renal impairment in patients undergoing PN or RN. Evidence acquisition A systematic review was conducted up to November 30, 2017 through PubMed, Scopus, and Embase databases, to identify eligible studies evaluating the role of biomarkers for the prediction of AKI after PN or RN. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria were applied to select articles. Evidence synthesis According to the study selection criteria, 10 publications were included with a total number of 728 patients. Incidence of AKI was 26.7% (range: 9–58%). Based on the evidence reviewed, serum cystatin C and urinary neutrophil gelatinase-associated lipocalin (NGAL) showed a significant correlation with serum creatinine rise postoperatively, emerging as potential noninvasive and early biomarkers of AKI in patients undergoing renal surgery. In this setting, serum cystatin C and urinary NGAL have preceded the rise in serum creatinine peak from 3 up to 24 h, even in case of mild renal damage. Conclusions The literature underlines the potential usefulness of biomarkers such as cystatin C and NGAL as promising and early tools to predict AKI after PN or RN. However, no strong evidence in support of their use is available to date and further investigations are awaited. Patient summary We looked at the role of biomarkers in predicting renal injury in patients undergoing partial or radical nephrectomy. Serum cystatin C and urinary neutrophil gelatinase-associated lipocalin have emerged as promising noninvasive, accurate, and early biomarkers.

The Predictive Role of Biomarkers for the Detection of Acute Kidney Injury After Partial or Radical Nephrectomy: A Systematic Review of the Literature.

Abstract The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms.

https://www.eneuro.org/content/eneuro/early/2022/12/07/ENEURO.0483-22.2022.full.pdf

The Neurotoxin DSP-4 Dysregulates the Locus Coeruleus-Norepinephrine System and Recapitulates Molecular and Behavioral Aspects of Prodromal Neurodegenerative Disease

Abstract The noradrenergic locus coeruleus (LC) is among the earliest sites of tau and α-synuclein pathology in Alzheimer’s disease (AD) and Parkinson’s disease (PD), respectively. The onset of these pathologies coincides with loss of noradrenergic fibers in LC target regions and the emergence of prodromal symptoms including sleep disturbances and anxiety. Paradoxically, these prodromal symptoms are indicative of a noradrenergic hyperactivity phenotype, rather than the predicted loss of norepinephrine (NE) transmission following LC damage, suggesting the engagement of complex compensatory mechanisms. Because current therapeutic efforts are targeting early disease, interest in the LC has grown, and it is critical to identify the links between pathology and dysfunction. We employed the LC-specific neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), which preferentially damages LC axons, to model early changes in the LC-NE system pertinent to AD and PD in male and female mice. DSP-4 (two doses of 50 mg/kg, one week apart) induced LC axon degeneration, triggered neuroinflammation and oxidative stress, and reduced tissue NE levels. There was no LC cell death or changes to LC firing, but transcriptomics revealed reduced expression of genes that define noradrenergic identity and other changes relevant to neurodegenerative disease. Despite the dramatic loss of LC fibers, NE turnover and signaling were elevated in terminal regions and were associated with anxiogenic phenotypes in multiple behavioral tests. These results represent a comprehensive analysis of how the LC-NE system responds to axon/terminal damage reminiscent of early AD and PD at the molecular, cellular, systems, and behavioral levels, and provides potential mechanisms underlying prodromal neuropsychiatric symptoms. 

https://www.eneuro.org/content/eneuro/10/1/ENEURO.0483-22.2022.full.pdf

It is well acknowledged that Alzheimer's Disease (AD) pathological processes start decades before clinical manifestations, but the brain mechanism of sporadic AD in midlife remains unclear. To address this gap, we examined whether risk factors for late-life AD are associated with disrupted connectivity between two key structures in AD pathophysiology -- the Locus Coeruleus (LC) and hippocampus -- and its role in cognition, in a cohort of middle-aged and cognitively healthy individuals. Detailed neuropsychological assessments and functional Magnetic Resonance Imaging were obtained at baseline (N=210), and two-years follow-up (N=188). Associations of cognition and LC--Hippocampus functional connectivity with apolipoprotein {epsilon}4 (APOE4) genotype, and dementia family history (FHD) were investigated using linear regression. Correlations between the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score and cognitive and functional measures were further investigated. APOE {epsilon}4 allele was significantly associated with better performance in verbal, spatial and relational memory. Higher CAIDE scores were significantly associated with worse performance in verbal, visuospatial functions and short-term (conjunctive) memory. The CAIDE dementia risk score moderated the relationship between cognition and LC--Hippocampus functional connectivity. In individuals with low (=<3)/high (>=8) CAIDE scores, higher functional connectivity was significantly associated with better/worse cognition. These results shed light on the brain mechanism of incipient AD neuropathology in individuals, who are at high risk for late-life dementia on the cardiovascular risk score, but presently cognitively healthy.

/pdf/disrupted-role-of-the-connectivity-between-the-locus-2ae4upgq.pdf

Disrupted role of the connectivity between the locus coeruleus and the hippocampus in cognition of healthy, middle-aged individuals at risk of dementia: the PREVENT-Dementia study

Noradrenergic and cholinergic systems take centre stage in neuropsychiatric diseases of ageing

Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark of several age-related neurodegenerative disorders, including Alzheimer's disease. However, a comprehensive neuropathological examination of the LC is difficult due to its small size and rod-like shape. To investigate the LC cytoarchitecture and tau cytoskeletal pathology in relation to possible propagation patterns of disease-associated tau in an unprecedented large-scale three-dimensional view, we utilized volume immunostaining and optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8+ pathological tau in the LC/pericoerulear region of 20 brains from Braak neurofibrillary tangle (NFT) stage 0-6. We demonstrate an intriguing morphological complexity and heterogeneity of AT8+ cellular structures in the LC, representing various intracellular stages of NFT maturation and their diverse transition forms. We describe novel morphologies of neuronal tau pathology such as AT8+ cells with fine filamentous somatic protrusions or with disintegrating soma. We show that gradual dendritic atrophy is the first morphological sign of the degeneration of tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective of the Braak NFT stage, tau pathology is more advanced in the dorsal LC that preferentially projects to vulnerable forebrain regions in Alzheimer's disease, like the hippocampus or neocortical areas, compared to the ventral LC projecting to the cerebellum and medulla. Moreover, already in the precortical Braak 0 stage, 3D analysis reveals clustering tendency and dendro-dendritic close appositions of AT8+ LC neurons, AT8+ long axons of NFT-bearing cells that join the ascending dorsal noradrenergic bundle after leaving the LC, as well as AT8+ processes of NFT-bearing LC neurons that target the 4th ventricle wall. Our study suggests that the unique cytoarchitecture, comprised of a densely packed and dendritically extensively interconnected neuronal network with long projections, makes the human LC to be an ideal anatomical template for early accumulation and trans-neuronal spreading of hyperphosphorylated tau. 

/pdf/spatiotemporal-characterization-of-cellular-tau-pathology-in-46ui0vof.pdf

Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus–pericoerulear complex by three-dimensional imaging

The aim of this study was to demonstrate the accuracy of NGAL in detecting Acute Kidney Injury (AKI) after urogenital robotic surgery in general anesthesia. Methods : A prospective longitudinal observational study, which included patients scheduled for elective robotic surgery under general anesthesia. The serum and urine NGAL at induction, 6 hours and 12 hours were determined. Serum creatinine was measured preoperatively and daily 4 days postoperatively. AKI was defined as the absolute growth of serum creatinine by 0.3 mg/dl over baseline within 48 hours postoperatively. Results : 24 patients were enrolled in the study. AKI occurred in 38% of patients. Serum NGAL increased significantly at 6 hours and 12h, compared to baseline, with a higher increase in the group of patents without AKI. There were no significant results for urine NGAL. A link was observed between the values of serum NGAL, with associated significance p<0.0001. The correlations between urine NGAL were not significant. The predictive value of NGAL, analyzed by cross-tabulation, OR was 3 for baseline value and 5.33 for the values measured at 6 hours and 12 hours, but with no statistical significance. Conclusions : The modifications of the NGAL levels, measured at 6 hours and 12 hours from the induction of anesthesia, were significant with more importance at 6 hours and in patients without AKI. Serum NGAL had no predictive value for AKI, but the risk to develop AKI was 3 times higher for baseline determination and 5 times at 6 and 12 hours.

/pdf/accuracy-of-neutrophil-gelatinase-associated-lipocalin-in-55phor4sqw.pdf

Accuracy of neutrophil gelatinase-associated lipocalin in detecting acute kidney injury after urogenital robotic assisted laparoscopic surgery under general anesthesia.

Objectives: The aim of the present study was to validate the sensitivity and specificity of the NMP22® BladderChek® test in our group of patients according to the tumoral stage and grade and to identify the patient categories that might benefit from the non-invasive nature of NMP22® BladderChek® test. Methods: Voided urine samples from 266 patients with imagistic suspicion of bladder cancer were collected to perform the NMP22® BladderChek® test. The nuclear matrix protein 22 (NMP22) levels were measured by a lateral flow immunochromatographic qualitative assay, using 10 U/ml as the cut-off value. After this patients underwent transurethral resection of bladder tumors (TUR-BT) follewed by histologic grading and tumor staging for a proper and optimal patient management. Sensitivity specificity and positive predictive value of the NMP22® BladderChek® test were defined for different tumoral stage and grade. Results: Two hundred thirty-eight of the 265 patients had urothelial malignancies (76 pTa, 81 pT1, 37 pT2, 32 pT3, 12 pT4, 27 pT0; 118 G1, 54 G2, 64 G3). The sensitivity was 0.629 [0.612; 0.629] for the NMP22® BladderChek® test while the specificity was equal to 1 [0.851; 1]. Positive predictive values was 1 [0.973; 1], and the negative predictive value was 0.235 [0.200; 0.235]. Conclusions : The results demonstrate that the even if the NMP22® BladderChek® is an easily applied test, giving diagnostic findings within 30 min, cannot be recommended for screening or surveillance in clinical routine use in non muscle invasive bladder cancer because of its poor sensitivity.

/pdf/validation-of-the-diagnostic-value-of-nuclear-matrix-protein-3p9eeax37o.pdf

Orsolya Maria Mihály

Papers

Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus–pericoerulear complex by three-dimensional imaging

Accuracy of neutrophil gelatinase-associated lipocalin in detecting acute kidney injury after urogenital robotic assisted laparoscopic surgery under general anesthesia.

Validation of the Diagnostic Value of Nuclear Matrix Protein 22 Depending on Tumoral Stage and Grade