Background/Aims: Basal cell carcinoma (BCC) is a frequent type of nonmelanoma skin cancer, which shows a greater prevalence in kidney-transplanted (KT) patients than in the general population. The ...study of this tumor in KT patients may allow us to understand the influence of the tumor inflammatory microenvironment on cancer behavior, and to design new image analysis methods to determine prognosis and apply personalized medicine. The major hypothesis of the present work is that antirejection drugs, by modifying the B-cell/T-cell balance, induce measurable differences in tumoral cell microarchitecture and in the inflammatory microenvironment in KT patients compared to nontransplanted controls. Methods: In this retrospective study in an Italian cohort including 15 KT patients and 15 control subjects from the general population who developed BCC, we analyzed tissue microarchitecture and inflammatory infiltrates of BCC using state-of-the-art nonlinear image analysis techniques such as fractal dimension and sample entropy of internuclear distances. Results: KT patients showed a nonsignificant trend to a greater number of nuclei in the basal cell layer compared to non-KT controls and subtle changes in the intact skin compared to controls. Similarly, the number of mitoses per unit length was almost doubled in the patients with KT compared to controls. However, when the number of mitotic cells was normalized by the total number of cells in the basal layer (mitotic index), these differences were not significant, although a clear trend was still present. Finally, KT patients showed a nonsignificant trend to an increased density of inflammatory cells close to the tumoral cell layer. When considering the intact skin, this difference was significant, with a 70% increase in the density of inflammatory cells. Conclusion: Data comparing the microarchitecture of BCC in normal subjects and KT patients are scanty, and the present study is the first to use nonlinear image analysis techniques to this aim. The observed differences underscore the relevance of T-cell suppression in cancer behavior. These data suggest that BCC develops in treated patients with specific biological characteristics which should be further analyzed in terms of therapeutic response.
Na+/Ca+ exchanger 3 (NCX3), one of the three isoforms of the NCX family, is highly expressed in the brain and is involved in the maintenance of intracellular Na+ and Ca2+ homeostasis. Interestingly, ...whereas the function of NCX3 under physiological conditions has been determined, its role under anoxia is still unknown. To assess NCX3 role in cerebral ischemia, we exposed ncx3-/- mice to transient middle cerebral artery occlusion followed by reperfusion. In addition, to evaluate the effect of ncx3 ablation on neuronal survival, organotypic hippocampal cultures and primary cortical neurons from ncx3-/- mice were subjected to oxygen glucose deprivation (OGD) plus reoxygenation. Here we report that ncx3 gene suppression leads to a worsening of brain damage after focal ischemia and to a massive neuronal death in all the hippocampal fields of organotypic cultures as well as in cortical neurons from ncx3-/- mice exposed to OGD plus reoxygenation. In addition, in ncx3-/- cortical neurons exposed to hypoxia, NCX currents, recorded in the reverse mode of operation, were significantly lower than those detected in ncx3+/+. From these results, NCX3 protein emerges as a new molecular target that may have a potential therapeutic value in modulating cerebral ischemia.
Chronic kidney disease (CKD) is a major clinical sign of patients with Bardet-Biedl syndrome (BBS), especially in those carrying BBS10 mutations. Twenty-nine patients with BBS and 30 controls ...underwent a serum-targeted metabolomic analysis. In vitro studies were conducted in two kidney-derived epithelial cell lines, where Bbs10 was stably deleted (IMCD3-Bbs10−/−cells) and over-expressed. The CKD status affected plasmatic metabolite fingerprinting in both patients with BBS and controls. Specific phosphatidylcholine and acylcarnitines discriminated eGFR decline only in patients with BBS. IMCD3-Bbs10−/ cells displayed intracellular lipidaccumulation, reduced mitochondrial potential membrane and citrate synthase staining. Mass-Spectrometry-based analysis revealed that human BBS10 interacted with six mitochondrial proteins, in vitro. In conclusion, renal dysfunction correlated with abnormal phosphatidylcholine and acylcarnitines plasma levels in patients with BBS; in vitro, Bbs10 depletion caused mitochondrial defects while human BBS10 interacted with several mitochondria-related proteins, suggesting an unexplored role of this protein.
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•Targeted Metabolomics reveals a unique serum fingerprinting of patients with BBS with CKD•Acylcarnitines are among the most significant alterations•In renal epithelial cells, Bbs10 depletion leads to mitochondrial abnormalities•Human BBS 10 interacts with six mitochondria-related proteins
Pathophysiology; Metabolomics
The total number of nephrons has been measured mainly from post-mortem studies and only in selected populations. Data from living subjects are scanty, and direct comparisons among different ...glomerular diseases are lacking. The present work exploits modern methodology to estimate the total nephron number in glomerulopathies with prevalent proteinuria/nephrotic syndrome versus glomerulopathies with nephritic syndrome (IgA nephropathy (IgAN), lupus nephritis), thus extending previous observations about the number and function of glomeruli in different physiological and pathological states.
This is a retrospective study based on one hundred and seven patients who have undergone renal biopsy. The glomerular density has been estimated from the biopsy specimens and the total cortical volume has been obtained from ultrasound recordings. Stereological methods have been applied to calculate the total number of nephrons and their volume. The correlation between clinical parameters and quantitative morphological data have studied using the Pearson correlation coefficient (
).
The total number of nephrons inversely correlated with the systolic blood pressure (
= -0.4,
< 0.05). In proteinuric diseases, such as focal segmental glomerulo-sclerosis (FSGS), membranous nephropathy (MN) and diabetes, the change in estimated GFR (eGFR) directly correlated with the total number of non-sclerotic glomeruli (NSG) (
= 0.62,
< 0.01), whereas in nephritic syndrome no significant correlation was observed. The alterations in eGFR occurring in nephritic syndromes such as IgAN cannot be explained on the basis of the number of NSG.
The fusion of the podocyte foot-processes that typically occurs in purely proteinuric diseases does not modify the glomerular filtration rate: therefore in these situations, the change in eGFR depends mainly on the number of available glomeruli. On the other side, the eGFR decrease occurring in nephritic syndromes, such as IgAN, cannot be explained simply on the basis of the number of NSG and likely depends on the substantial involvement of the mesangial axis. Future studies should verify whether these changes are reversible with appropriate therapy, thus reversing eGFR decrease.
Recent studies suggest a link between chronic kidney disease and brain dysfunctions such as depression and cognitive problems. A review of medieval and early-modern historical figures with aspects of ...both kidney disease (gout and edema dropsy) and depression (melancholia) shows that these conditions were observed together in the past.
References to the diseases of gout, dropsy, and melancholia were compared in literature on historical subjects. Case studies are reported to detail a previously unremarked com-bination of current kidney disease and depression comorbidity in historical writings.
The poet Boccaccio had gout and melancholia, and some descendants of the Portuguese Avis and Spanish Trastàmara dynasties, known for melancholia and madness, also had gout and dropsy. Historical case series of causes of death for sultans of the Ottoman Empire suggest an association among dropsy, gout, and melancholia.
In this article, we reviewed the medical research on the comorbidity of kidney disease and depression and shared case studies of historical figures with these conditions and posit not previously noted data supporting comorbidity observations in historical writings.
Animal models are useful for characterizing neural substrates of neuropsychiatric disorders. Several models have been proposed for the study of Attention Deficit Hyperactivity Disorder (ADHD). The ...models can be divided into various groups: (i) genetically derived hyperactivity/ inattention, (ii) animal models showing symptoms after pharmacological intervention, and (iii) those based on spontaneous variations in a random population. Spontaneously hypertensive (SHR) and Naples High Excitability (NHE) rats show behavioral traits featuring the main aspects of ADHD in humans but show different changes in dopamine (DA) systems. In fact, the enzyme tyrosine hydroxylase is hyperexpressed in NHE rats and hypoexpressed in SHR. The DA transporter is hyperexpressed in both lines, although in the SHR, DAT activity is low (reduced DA uptake). The DA levels in the striatum and prefrontal cortex are increased in the juvenile SHR, but are decreased in handled young and non-handled older animals. The mRNA of the D1 DA receptor is upregulated in the prefrontal cortex of SHR and down-regulated in NHE. The D2 DA receptors are likely to be hypofunctioning in SHR, although the experimental evidence is not univocal, whereas their mRNA is hyperexpressed in NHE. Thus, in SHR both the mesocortical and mesolimbic DA pathways appear to be involved, whereas in NHE only the mesocortical system. To understand the effects of methylphenidate, the elective ADHD drug treatment in humans, in a dysfunctioning DA system, we realized a simple mathematical model of DA regulation based on experimental data from electrophysiological, cyclic voltammetry, and microdialysis studies. This model allows the estimation of a higher firing frequency of DA neurons in SHR rats and suggests that methylphenidate increases attentive processes by regulating the firing rate of DA neurons.
Abstract Background and Aims In both classical hemodialysis (HD) and its high convective version, the hemodiafiltration (HDF), the unavoidable contact of blood cells with the filters (e.g. ...polysulfone), may cause the formation of microaggregates and the release of Inflammatory cytokines. Reducing inflammation and thrombus formation is essential, as these may change the cardiovascular risk of patients undergoing chronic HD. To overcome this problem, removing plasma proteins with greater molecular weight, thereby modifying the protein network around blood cells, might be helpful. Method Synthetic dialyzers (FX 80 CorDiax Fresenius Medical Care, medium-cutoff filter Theranova 400 Baxter, Elisio 17-H Nipro, and BG-U 1.6 Toray) have been compared regarding their effects on white blood cell types. We designed a retrospective, dual-center clinical study on patients in ESRD needing substitutive therapy. Groups comparable for age, blood pressure, and body weight have been compared. Changes in albumin, Hb, neutrophils, eosinophils, basophils, monocytes, and platelets have been analysed one month after the treatment. Results The Theranova treatment decreased lymphocytes but was also observed to increase neutrophils and MCV. Platelet count was highest with Elisio-H filters, whereas they were comparable among the other groups. Correlation analysis showed a significant association between platelet counts, neutrophils, and monocytes in all groups. Conversely, the correlation between eosinophils and lymphocytes was significant for all groups except for the Theranova filters. Furthermore, the dialyzers inulin (5.2kDa) clearance was negatively linearly correlated to the lymphocyte counts. Conclusion The recent introduction of MCO filters offers the clinician an adjunctive possibility to modify blood composition in terms of plasma composition and different white blood cells. Further studies may use these unique characteristics in new clinical settings.
MO216PRELIMINARY STUDY OF THE GLYMPHATIC SYSTEM IN CKD Buonincontri, Veronica; Viggiano, Davide; Capasso, Giovambattista
Nephrology, dialysis, transplantation,
05/2021, Volume:
36, Issue:
Supplement_1
Journal Article
Peer reviewed
Abstract
Background and Aims
The glymphatic system is a network of extracellular spaces between neurons, glial cells, and capillaries that promotes the elimination of soluble molecules from the ...brain. Its dysfunction is probably relevant for neurodegenerative diseases such as Alzheimer's disease (AD). It is widely accepted that cognitive impairment accompanies chronic kidney disease (CKD). CKD is also a risk factor for dementia. However, the role of the glymphatic system in this process is unknown. A recent method to study the glymphatic system in human subjects has been proposed based on Diffusion Tensor Imaging (DTI) data and water diffusion calculation along with perivascular spaces. This approach is based on calculating a diffusion index named ALPS and showed that the glymphatic flow is reduced in MCI.
Method
To analyze the role of glymphatic system in CKD patients, we took advantage of the Alzheimer's Disease Neuroimaging Initiative (ADNI). ADNI is a longitudinal multicenter study helping researchers to monitor Alzheimer's disease and Mild Cognitive Impairment (MCI) progression. This database has a cohort of control patients and MCI patients, among which several patients with CKD stage II-III were identifiable from the creatinine values. Patients with Alzheimer's disease were excluded for this study. Among the control and MCI patients, we identified 12 CKD patients and pair-matched 12 non-CKD patients comparable for age, gender, and MoCA score. Magnetic resonance data with DTI sequences were retrieved for all patients, and the glymphatic system was characterized by the ALPS index. Tensor values were calculated using the FSL software; the diffusion values were calculated on tensor images using the ImageJ software. Differences in ALPS between CKD and non-CKD patients with and without MCI were tested.
Results
Analysis of DTI data confirmed that control patients without CKD had lower ALPS values when MCI was present compared to the non-MCI patients, suggesting a reduction of water diffusion in the glymphatic system. However, the presence of CKD had a different effect: in the absence of MCI, CKD did not modify ALPS values compared to non-CKD patients. At variance, in patients with MCI, CKD resulted in a significant increase of water diffusion in the glymphatic system compared to the controls.
Conclusion
In this preliminary study, MCI and CKD exerted opposite effects on the diffusion of water within the glymphatic system: MCI was accompanied by a reduction of water diffusion whereas CKD by an increased diffusion in the glymphatic spaces.
It is possible that small modification of water balance in CKD may be responsible for the increased diffusion of water in glymphatics in CKD. Further studies are needed to verify whether this unexpected phenomenon may modify cognitive function with a mechanism rather different from Alzheimer's disease.
Abstract
Background and Aims
Mild Cognitive Impairment (MCI) has been found to be highly prevalent amongst patients with Chronic Kidney Disease (CKD). In this cohort, the prevalence of MCI was ...estimated to be between 30% and 63%. Mild cognitive impairment is an intermediate state between normal aging and dementia. An individual suffering from MCI has difficulty in remembering, sustaining attention, or decision making which can negatively affect their daily lives.
The aim of this study was to verify the role of different glomerular diseases diagnosed by kidney biopsy on the MCI through a retrospective study.
Method
We recruited 45 patients with bioptic diagnosis of the following glomerular diseases: Focal Segmental Glomerulo Sclerosis (FSGS), minimal change disease (MCD), membranous glomerular disease (MG), IgA nephropathy. The renal function was analyzed using clinical variables, while Cognitive functions using the MoCA test. Patients were divided into two groups based on 24h proteinuria.
Results
The MoCA score was directly correlated to the uric acid levels (R=0.13; p=0.03). The MoCa score in the group with higher proteinuria levels was significantly lower than those of the group with lower proteinuria levels (p = 0.03). Finally, the MoCA score in subjects with FSGS or MCD is significantly higher compared the other groups (p<0.05).
Conclusion
Our data suggest that serum uric acid and proteinuria in glomerular diseases influence cognitive functions. Interestingly, uric acid plays a neuroprotective role, as low levels of uric acid reduce the MoCA score. This result agrees with previous observations of a protective role of uric acid on dopamine neurons. Conversely, the extent proteinuria seems to negatively affect cognitive functions, suggesting a role of the endothelial dysfunction. Finally, glomerulopathies with a lower degree of inflammation (FSGS, MCD) have minor impact on cognitive functions.
KCNQ2 and KCNQ3 subunits encode for the muscarinic-regulated current (IKM), a sub-threshold voltage-dependent K⁺ current regulating neuronal excitability. In this study, we have investigated the ...involvement of IKM in dopamine (DA) release from rat striatal synaptosomes evoked by elevated extracellular K⁺ concentrations (K⁺e) and by muscarinic receptor activation. ³Hdopamine (³HDA) release triggered by 9 mmol/L K⁺e was inhibited by the IKM activator retigabine (0.01-30 μmol/L; Emax = 54.80 ± 3.85%; IC₅₀ = 0.50 ± 0.36 μmol/L). The IKM blockers tetraethylammonium (0.1-3 mmol/L) and XE-991 (0.1-30 μmol/L) enhanced K⁺-evoked ³HDA release and prevented retigabine-induced inhibition of depolarization-evoked ³HDA release. Retigabine-induced inhibition of K⁺-evoked ³HDA release was also abolished by synaptosomal entrapment of blocking anti-KCNQ2 polyclonal antibodies, an effect prevented by antibody pre-absorption with the KCNQ2 immunizing peptide. Furthermore, the cholinergic agonist oxotremorine (OXO) (1-300 μmol/L) potentiated 9 mmol/L K⁺e-evoked ³HDA release (Emax = 155 ± 9.50%; EC₅₀ = 25 ± 1.80 μmol/L). OXO (100 μmol/L)-induced ³HDA release enhancement was competitively inhibited by pirenzepine (1-10 nmol/L) and abolished by the M₃-preferring antagonist 4-diphenylacetoxy N-methylpiperidine methiodide (1 μmol/L), but was unaffected by the M₁-selective antagonist MT-7 (10-100 nmol/L) or by Pertussis toxin (1.5-3 μg/mL), which uncouples M₂- and M₄-mediated responses. Finally, OXO-induced potentiation of depolarization-induced ³HDA release was not additive to that produced by XE-991 (10 μmol/L), was unaffected by retigabine (10 μmol/L), and was abolished by synaptosomal entrapment of anti-KCNQ2 antibodies. Collectively, these findings indicate that, in rat striatal nerve endings, IKM channels containing KCNQ2 subunits regulate depolarization-induced DA release and that IKM suppression is involved in the reinforcement of depolarization-induced DA release triggered by the activation of pre-synaptic muscarinic heteroreceptors.
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