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Neurocognitive disorders are frequent among chronic kidney disease (CKD) patients. Identifying and characterizing cognitive impairment (CI) can help to assess the ability of adherence to CKD risk reduction strategy, identify potentially reversible causes of cognitive decline, modify pharmacotherapy, educate the patient and caregiver and provide appropriate patient and caregiver support. Numerous factors are associated with the development and progression of CI in CKD patients and various conditions can influence the results of cognitive assessment in these patients. Here we review clinical warning signs that should lead to cognitive screening; conditions frequent in CKD at risk to interfere with cognitive testing or performance, including specificities of cognitive assessment in dialysis patients or after kidney transplantation; and available tests for screening and observed cognitive patterns in CKD patients., Graphical Abstract Graphical abstract

Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut-brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system. Funding Agencies|COST Action CA19127-Cognitive Decline in Nephro-Neurology: European Cooperative Target (CONNECT)

Background and Aims Mild Cognitive Impairment (MCI) is a common finding in chronic kidney disease (CKD) patients. Indeed, CKD represents a relevant risk factor for developing dementia and MCI. Cholinesterase inhibitors, such as rivastigmine, are among the few drugs approved for the treatment of dementia and MCI. Rivastigmine is also used to treat vascular dementia because it protects subcortical brain structures. Data are scanty regarding the use of rivastigmine in CKD patients with MCI and are much needed to guide the therapy for MCI in this cohort of patients. Method This retrospective case-control study compared the effects of rivastigmine on cognitive functions in MCI patients with CKD (stage III-IV; n= 20) and without CKD (n=21, control group), comparable for the extent of cognitive impairment (indexed by Montreal Cognitive Assessment, MoCA), age (range 18-65 years), gender, weight, and comorbidities. Patients under treatment with rivastigmine and with a baseline MoCA score available were included in the study. Exclusion criteria were ictus, psychiatric or other neurological conditions, heart failure, liver failure, severe obesity, anemia, electrolyte disorders, cancer, dialysis, and other severe comorbidities. Laboratory test data (glycemia, cholesterol, hemoglobin, proteinuria, creatinine) were used to characterize the two populations. MCI was defined as a MoCA score between 21-26. The cognitive screening was available at baseline (before treatment) and during a follow-up in a range of three-six months after the start of the treatment. CKD was defined by eGFR < 60 mL/min/1.73m2. Results The follow-up timing for cognitive screening was not statistically different between the two cohorts. The control group (MCI without CKD) showed a small, significant improvement in the MoCA score after treatment (baseline MoCA: 22.9±0.5, follow-up MoCA: 23.5±0.5, p=0.02, t-test for paired data). At variance, the MCI-CKD group showed a significant improvement in the MoCA score (baseline MoCA=23±0.4, follow-up MoCA=24.3±0.4, p Accordingly, the extent of improvement of MoCA score after rivastigmine was inversely correlated to the eGFR (r = -0.23). Conclusion A significant improvement in MoCA score accompanied treatment with rivastigmine in the CKD group. More extensive population studies are needed to verify the greater efficacy of Acetylcholinesterase inhibitors in this population.

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.

Background and Aims The term "inflammation" is undoubtedly one of the oldest medical terms and yet in use. However, its meaning has changed over the centuries. This work gives a historical and critical view of the concept of inflammation, with particular reference to kidney diseases. Method The term "inflammation" was used in Galenic medicine to specify a collection of symptoms. Celsus (c. 25 BC – c. 50 AD) described "rubor et tumor cum calor et dolor", but the list became much longer in subsequent Galenic scholars. It is interesting to note that one of the inflammation symptoms, "tumor," was then used to indicate cancer (tumor=swelling due to a mass or due to edema). Virchow (1821 –1902) is often quoted for introducing a fifth symptom, "function Lasa", but his significant contribution relies on introducing the microscope to study diseases: thanks to this instrument, the paradigm of inflammation was undergoing a revolution. Thereby, the definition of inflammation shifted from a pure collection of symptoms to a histopathological classification, characterized by the tissue "inflammatory infiltrates" with subcategories according to the cell types involved. Numerous authors added their names to pathology textbooks when describing a new kind of cellular infiltration. Overall, the tremendous success of the histopathologic paradigm of inflammation or "inflammatory infiltrates" was the possibility to contain and revert this phenomenon with corticosteroids (with few exceptions). Subsequently, specific drugs were proposed for each inflammatory infiltrate. This type of paradigm is still used today to define, e.g., tubulointerstitial nephritis or intra- and peri-glomerular inflammations. The subsequent classification of inflammatory infiltrates using immunohistochemistry did not modify our classification system (the distinction of, e.g., CD20 lymphocytes from CD4 T-cells is not used, unfortunately, in today's classification system). Results Towards the 1940s, Avery et al. recognize that some plasma proteins (specifically the famous C-reactive protein) increase during acute infection, which is a typical inflammatory state. This observation led to a new "molecular definition of inflammation". The idea to identify the presence of inflammatory infiltrates in tissues just by looking at plasma constituents had great success: after all, the histological processing of tissues was no longer needed. Even though many authors were alerting that these plasma constituents are often increased even in the absence of any "inflammatory infiltrate", the plasma proteins were so easily accessible that the new direction was not modifiable. A modern generalization of this type of approach is called "liquid biopsy, " even though it is not limited to the inflammatory states, but to a larger number of identifiable diseases today only histologically. The effect of the new "molecular" definition of inflammation was that a large number of diseases without significant inflammatory infiltrates (such as obesity, atherosclerosis, aging, dialysis, and chronic kidney disease) are notwithstanding accompanied by the increase of plasma proteins labeled as "inflammatory". Therefore, the list of "inflammatory" diseases (in the new terms) is now much more extensive. The price for such enlargement of conditions is that most new entries do not respond to steroids or other anti-inflammatory drugs. Conclusion The new definition of" inflammatory disease" comprises classical steroid-dependent disorders characterized by inflammatory infiltrates and new conditions with minimal inflammatory infiltrates plus the presence of "inflammatory" plasma proteins plus little response to steroids. It might be beneficial to distinguish these types of inflammation.

Background and Aims Chronic kidney disease (CKD) is a systemic condition because it modifies all organs' function due to an imbalance in plasma volume, electrolytes, hormones, and proteins. Indeed, at the nervous system level, mild cognitive impairment (MCI), sleep disorders and depression often accompany CKD. MCI partially explains the low quality of life of CKD patients, comparable to that of metastatic cancer patients. Mild Cognitive Impairment (MCI) has a high prevalence in this cohort (27-62%). Nevertheless, scattered literature data suggest that CKD patients can also have poor motor control, evidenced by a higher risk of falls, postural instability, reduced gait speed. In this cohort, few data are available regarding the motor circuits called central pattern generators, which control physiological tremor. Specifically, uraemic encephalopathy accentuates physiological tremor, which is regulated by central and peripheral oscillators. Overall, subtle changes in motor control often accompany other forms of MCI. Therefore, this study aimed at evaluating the effects of chronic kidney disease on cognitive and motor functions using up-to-date technologies to record physiological tremor and innovative data analysis. Method This retrospective case-control study enrolled 313 patients (139 controls, 79 CKD patients stage III-IV, 35 kidney transplant (Tx), 60 dialysis (HD) patients). These groups were comparable for age and weight. Creatininemia, azotemia, LDL, HDL, hemoglobin, and proteinuria were used for correlative analyses. We evaluated the chronotype using the Morningness-Eveningness Questionnaire (MEQ) and the degree of sleepiness using the Epworth Sleepiness Scale (ESS). Cognitive impairment was assessed by the Montreal Cognitive Assessment test (MoCA). Cognitive domains of the MoCA score were projected onto brain regions using CerebroViz library in R and a new transformation matrix derived from fMRI literature data. UMAP algorithm was used to identify patients' subgroups. The physiological tremor was recorded on patients maintaining the dominant arm extended using the smartphone App Phyphox. The tremor frequency spectrum was extracted by Fourier analysis. Results The sleepiness score (ESS) was significantly increased in HD (ESS = 5±0.4) compared to the healthy controls (ESS= 4±0.41) whereas was not significantly modified in CKD patients (3.24± 0.32). The chronotype was also not significantly different among the various groups. The mean score of the MoCA test was significantly lower in CKD, Tx, and HD groups (CKD MoCA =24.5±0.3; Tx MoCA =25.4±0.6; HD MoCA =24.6±0.7) than controls (MoCA score=28±0.1). A different pattern of impairment in the cognitive domains of MoCA was evidenced in the various groups using the CerebroViz projection and UMAP tools. MoCA score was inversely correlated with proteinuria (Pearson coefficient=-0.47; p The higher frequencies of the physiological tremor (11-13 Hz) were significantly more represented in Tx patients compared to controls (p Conclusion Our results suggest that CKD patients present altered cognitive and motor control patterns, linked in part to the proteinuria level, suggesting a pathogenetic role of endothelial dysfunction. The characteristic motor, sleepiness and cognitive patterns of HD patients might be due to the arteriovenous fistula or the other peculiarities of these patients. These results might help identify new early markers of brain dysfunction in these patients, with the possibility of delaying or reversing cognitive decay.

Background and Aims Kidney plays a central role on the maintenance of water homeostasis, acid-base and electrolytes balances through the activity of different types of ion channels/transporters expressed along the nephron segments. Mutations in genes encoding these transporters could subsequently lead to aberrant transporter activities, resulting in abnormal renal handling of electrolytes, thus represent monogenic form of rare kidney diseases. Accumulating number of mutations identified in genes responsible for such monogenic disorders demonstrated that eventual disease phenotypes may vary according to the type and localization of the mutation within the gene. Thus, careful evaluation of gene variation would be crucial prior to designing the strategy for the therapy in each case. Here we present various mutations from our patients, identified in genes including kcnj10, SLC12A1, SLC26A4 and clcn7 which are associated with rare tubulopathies EAST/SeSAME syndrome, Bartter’s syndrome, Pendred syndrome and Fanconi syndrome, respectively. In order to explore molecular mechanisms underlying the observed disease conditions in our patients, we have performed computational modeling analyses of these mutations in comparison with wild-type models. Method Three-dimensional homology models of Kir4.1, NKCC2, Pendrin and CLC-7 proteins were generated by Swiss-Model protein structure homology-modelling server (http://swissmodel. expasy.org) and I-TASSER server (https://zhanglab.ccmb.med.umich.edu/I-TASSER/). Disease-related mutations including novel mutations identified from our patients were mapped onto the three-dimensional models and compared with wild-type models in terms of atomic interactions as well as secondary, tertiary and quaternary structures. Furthermore, we assessed possible effects of missense mutations on the function of ion channels/transporters using online bioinformatic prediction tools PolyPhen-2, Mutation taster, PROVEAN and SIFT. Results The three-dimensional model comparison between wild-type Kir4.1 and Ala167Val variant, which is related to EAST/SeSAME syndrome, revealed that Ala167Val located at the junction between transmembrane domain 2 (TM2) and C-terminus is predicted not to interrupt the sequence of the hydrogen bonds, thus not altering the TM2 alpha-helix structure. In addition, while PolyPhen-2 and Mutation taster evaluated Ala167Val as ‘probably damaging’, PROVEAN and SIFT predicted Ala167Val as ‘neutral’ and ‘tolerated’. These observations are in line with the clinical data demonstrating the milder phenotype in patients with Ala167Val mutation compared with the ones harboring frameshift mutations leading to truncated Kir4.1 channel (Figure. 1). Furthermore, computational modeling of wild-type NKCC2 and frameshift mutation Arg302Glyfs*3 variant clearly demonstrated that Arg302Glyfs*3 results in a loss of large part of the protein, indicating that NKCC2-Arg302Glyfs*3 is practically nonfunctional (Figure. 2). Conclusion Computational modeling of disease-related mutations in various ion channels/transporters represents a novel, powerful approach for comprehensive interpretation of the disease phenotypes observed in patients with rare tubulopathies. In addition, combination of in silico modeling and clinical data could provide us with further insight into molecular mechanisms underlying the renal transporter activities. Furthermore, this in silico computational modeling approach can be applicable and suggestive for novel pharmacological intervention as well as the visual disease severity assessment.

Dopamine (DA) is a key neurotransmitter involved in multiple physiological functions including motor control, modulation of affective and emotional states, reward mechanisms, reinforcement of behavior, and selected higher cognitive functions. Dysfunction in dopaminergic transmission is recognized as a core alteration in several devastating neurological and psychiatric disorders, including Parkinson’s disease (PD), schizophrenia, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and addiction. Here we will discuss the current insights on the role of DA in motor control and reward learning mechanisms and its involvement in the modulation of synaptic dynamics through different pathways. In particular, we will consider the role of DA as neuromodulator of two forms of synaptic plasticity, known as long-term potentiation (LTP) and long-term depression (LTD) in several cortical and subcortical areas. Finally, we will delineate how the effect of DA on dendritic spines places this molecule at the interface between the motor and the cognitive systems. Specifically, we will be focusing on PD, vascular dementia, and schizophrenia.

BackgroundUrine concentrating defect is a common dysfunction in ciliopathies, even though its underlying mechanism and its prognostic meaning are largely unknown. This study assesses renal function in a cohort of 54 Bardet–Biedl syndrome (BBS) individuals and analyses whether renal hyposthenuria is the result of specific tubule dysfunction and predicts renal disease progression.MethodsThe estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (ACR) and maximum urine osmolality (max-Uosm) were measured in all patients. Genetic analysis was conducted in 43 patients. Annual eGFR decline (ΔeGFR) was measured in patients with a median follow-up period of 6.5 years. Urine aquaporin-2 (uAQP2) excretion was measured and the furosemide test was performed in patients and controls.ResultsAt baseline, 33 (61.1%), 12 (22.2%) and 9 (16.7%) patients showed an eGFR >90, 60–90 and 30 mg/g and 55.8% of patients showed urine concentrating defect in the absence of renal insufficiency. Baseline eGFR, but not max-Uosm, correlated negatively with age. Conversely, truncating mutations affected max-Uosm and showed a trend towards a reduction in eGFR. Max-Uosm correlated with ΔeGFR (P ConclusionsHyposthenuria is a warning sign predicting poor renal outcome in BBS. The pathophysiology of this defect is most likely beyond defective tubular function.

Cognitive impairment is an increasingly recognized major cause of chronic disability and is commonly found in patients with chronic kidney disease (CKD). Knowledge of the relationship between kidney dysfunction and impaired cognition may improve our understanding of other forms of cognitive dysfunction. Patients with CKD are at an increased risk (compared with the general population) of both dementia and its prodrome, mild cognitive impairment (MCI), which are characterized by deficits in executive functions, memory and attention. Brain imaging in patients with CKD has revealed damage to white matter in the prefrontal cortex and, in animal models, in the subcortical monoaminergic and cholinergic systems, accompanied by widespread macrovascular and microvascular damage. Unfortunately, current interventions that target cardiovascular risk factors (such as anti-hypertensive drugs, anti-platelet agents and statins) seem to have little or no effect on CKD-associated MCI, suggesting that the accumulation of uraemic neurotoxins may be more important than disturbed haemodynamic factors or lipid metabolism in MCI pathogenesis. Experimental models show that the brain monoaminergic system is susceptible to uraemic neurotoxins and that this system is responsible for the altered sleep pattern commonly observed in patients with CKD. Neural progenitor cells and the glymphatic system, which are important in Alzheimer disease pathogenesis, may also be involved in CKD-associated MCI. More detailed study of CKD-associated MCI is needed to fully understand its clinical relevance, underlying pathophysiology, possible means of early diagnosis and prevention, and whether there may be novel approaches and potential therapies with wider application to this and other forms of cognitive decline.

A major paradigm in nephrology states that the loss of filtration function over a long time is driven by a persistent hyperfiltration state of surviving nephrons. This hyperfiltration may derive from circulating immunological factors. However, some clue about the hemodynamic effects of these factors derives from the effects of so-called nephroprotective drugs. Thirty years after the introduction of Renin-Angiotensin-system inhibitors (RASi) into clinical practice, two new families of nephroprotective drugs have been identified: the sodium-glucose cotransporter 2 inhibitors (SGLT2i) and the vasopressin receptor antagonists (VRA). Even though the molecular targets of the three-drug classes are very different, they share the reduction in the glomerular filtration rate (GFR) at the beginning of the therapy, which is usually considered an adverse effect. Therefore, we hypothesize that acute GFR decline is a prerequisite to obtaining nephroprotection with all these drugs. In this study, we reanalyze evidence that RASi, SGLT2i, and VRA reduce the eGFR at the onset of therapy. Afterward, we evaluate whether the extent of eGFR reduction correlates with their long-term efficacy. The results suggest that the extent of initial eGFR decline predicts the nephroprotective efficacy in the long run. Therefore, we propose that RASi, SGLT2i, and VRA delay kidney disease progression by controlling maladaptive glomerular hyperfiltration resulting from circulating immunological factors. Further studies are needed to verify their combined effects.

Prep1 is a homeodomain transcription factor which has an important role in hindbrain development. Prep1 expression is also kept in adult mouse brain and in particular within the olfactory bulbs. Moreover, many Prep1 neurons co-localize with Calbindin-positive periglomerular interneurons in olfactory glomerular layer. However, Prep1 function in this brain region is still unknown. In this study, we show that Prep1 hypomorphic heterozygous (Prep1i/+) mice express low levels of protein and feature a 30% reduction of olfactory bulb area, compared to WT mice. In addition, Prep1i/+ mice olfactory bulb histological analysis indicated a 20% lower cytochrome C oxidase activity within the glomerular layer, accompanied by a reduced number of periglomerular interneurons, compared to the WT littermates. Consistently, olfactory perception test highlighted that Prep1 hypomorphic heterozygous mice display a scant ability to distinguish odors, which significantly impacts on feeding behavior, as Prep1i/+ mice revealed a reduced preference for high-fat food. Analysis of BDNF signaling, which represents the main molecular mediator of olfactory plasticity, showed that Prep1i/+ mouse olfactory bulbs feature a 30% reduction of TrkB receptor levels and a decreased activation of ERK1/2. Similarly, overexpression of Prep1 in mouse neuronal cells (N2A) caused an increase of TrkB expression levels, BDNF-induced ERK phosphorylation, and cell viability, compared to control cells. We conclude that Prep1 deficiency alters olfactory morpho-functional integrity and olfaction-mediated eating behavior by affecting BDNF-TrkB signaling. Prep1 could, therefore, play a crucial role in behavioral dysfunctions associated to impaired responsiveness to BDNF. Electronic supplementary material The online version of this article (10.1007/s12035-018-0873-7) contains supplementary material, which is available to authorized users.

Dendritic spines, small protrusions emerging from the dendrites of most excitatory synapses in the mammalian brain, are highly dynamic structures and their shape and number is continuously modulated by memory formation and other adaptive changes of the brain. In this study, using a behavioral paradigm of motor learning, we applied the non-linear analysis of dendritic spines to study spine complexity along dendrites of cortical and subcortical neural systems, such as the basal ganglia, that sustain important motor learning processes. We show that, after learning, the spine organization has greater complexity, as indexed by the maximum Lyapunov exponent (LyE). The positive value of the exponent demonstrates that the system is chaotic, while recurrence plots show that the system is not simply composed by random noise, but displays quasi-periodic behavior. The increase in the maximum LyE and in the system entropy after learning was confirmed by the modification of the reconstructed trajectories in phase-space. Our results suggest that the remodeling of spines, as a result of a chaotic and non-random dynamical process along dendrites, may be a general feature associated with the structural plasticity underlying processes such as long-term memory maintenance. Furthermore, this work indicates that the non-linear method is a very useful tool to allow the detection of subtle stimulus-induced changes in dendritic spine dynamics, giving a key contribution to the study of the relationship between structure and function of spines.

Kidney transplant (KT) recipients have an increased risk for specific types of cancer. Some forms of incident cancer are similarly present in other diseases where T-cells are depleted, such as HIV-infection: specifically, non-Hodgkin lymphoma and Kaposi’s sarcoma. Conversely, other forms of highly incident cancers in KT patients, primarily non-melanoma skin cancer (squamous cell carcinoma and basal cell carcinoma), are specific to this condition. By comparing HIV-related cancers, general cancer incidence, and the association of immunotherapy with cancer incidence, we suggest that the high incidence of non-melanoma skin cancer seen in KT patients is mediated by off-target effects of calcineurin inhibitors in the skin, combined with a “permissive” cancer microinflammatory environment.

Background/aim Squamous cell carcinoma (SCC) is highly prevalent in kidney transplant patients (KT). It is characterized by the presence of an inflammatory infiltrate. In this study, we examined the presence of similar infiltrates in intact skin, which could be regarded as a precancerous step. Patients and methods We retrospectively analyzed skin biopsies of 19 non-transplanted patients with a diagnosis of SCC or basal cell carcinoma (BCC) and 17 KT with either SCC or BCC. Results KT showed increased inflammatory infiltrate in the subepithelial region, compared to non-transplanted patients. The density of basal cell nuclei was also different among the four groups with an interaction effect between tumor type and transplantation. The extent of inflammatory infiltrates did not correlate with the eGFR and proteinuria. Conclusion KT with a non-melanoma skin cancer show increased intact skin inflammatory infiltrate and alterations in the density of the basal cell layer compared to non-transplanted patients.

Assessment of kidney function in oncology patients is a fundamental factor in profiling the survival risk, determining the appropriate dose of chemotherapeutic drugs, and defining a patient eligibility for clinical trials with novel agents. Both overestimation and underestimation of kidney function may affect the treatment efficacy and outcomes. Overestimation may lead to overdosing or inappropriate agent selection and the corresponding toxicity, whereas underestimation may be responsible for underdosing or inappropriate agent exclusion and subsequent treatment failure. This is of utmost importance in patients with cancer. Evaluation of kidney function is not only limited to the estimation of glomerular filtration rate or creatinine clearance. An accurate assessment of kidney function is advisable to reduce variability in decision making and ultimately the therapeutic outcomes of toxicity and clinical benefit. Therefore, additional studies are needed to investigate the validity of currently used formulas estimating kidney function in this population as well as their applicability to traditional chemotherapy, novel targeted therapies, and immunotherapies. Because of rapid discovery and development of new cancer agents, a reliable and comprehensive manner to screen for potential nephrotoxicity is critically important. As kidney function not only is limited to glomerular filtration rate changes but also involves tubular and even vascular dysfunction, urinalysis and kidney imaging studies should also be considered before therapeutic decisions are taken. However, several questions remain regarding these new technologies such as kidney-on-a-chip systems for the assessment of kidney function and injury, particularly in oncology, and it has yet to be implemented in clinical practice.

Network Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein–protein interaction networks, correlation‐based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approaches to Omics Big Data (including genetics, epigenetics, transcriptomics, metabolomics, and proteomics) using computational biology tools and, thereby, has the potential to provide improvements in the diagnosis, prognosis, and treatment of complex diseases. We discuss briefly the types of molecular data that are used in molecular network analyses, survey the analytical methods for inferring molecular networks, and review efforts to validate and visualize molecular networks. Successful applications of molecular network analysis have been reported in pulmonary arterial hypertension, coronary heart disease, diabetes mellitus, chronic lung diseases, and drug development. Important knowledge gaps in Network Medicine include incompleteness of the molecular interactome, challenges in ideNetwork Medicine applies network science approaches to investigate disease pathogenesis. Many different analytical methods have been used to infer relevant molecular networks, including protein–protein interaction networks, correlation‐based networks, gene regulatory networks, and Bayesian networks. Network Medicine applies these integrated approaches to Omics Big Data (including genetics, epigenetics, transcriptomics, metabolomics, and proteomics) using computational biology tools and, thereby, has the potential to provide improvements in the diagnosis, prognosis, and treatment of complex diseases. We discuss briefly the types of molecular data that are used in molecular network analyses, survey the analytical methods for inferring molecular networks, and review efforts to validate and visualize molecular networks. Successful applications of molecular network analysis have been reported in pulmonary arterial hypertension, coronary heart disease, diabetes mellitus, chronic lung diseases, and drug development. Important knowledge gaps in Network Medicine include incompleteness of the molecular interactome, challenges in identifying key genes within genetic association regions, and limited applications to human diseasesntifying key genes within genetic association regions, and limited applications to human diseases

The term "inflammation" is certainly one of the oldest medical terms still in use. However, its meaning has changed over the centuries. This work gives a historical and critical review of the concept of inflammation, with special reference to kidney diseases. Over time the definition of inflammation has shifted from a pure collection of symptoms to a histopathological definition, characterized by the tissue "inflammatory infiltrates" and different subcategories according to the cell type involved. The advantages of this classification are the generally good response to corticosteroids (with only a few exceptions) and the availability of specific drugs for each inflammatory infiltrate. Finally, a "molecular" definition of inflammation has arisen, where the inflammatory infiltrates make room to a plethora of plasma mediators. The authors show that the use of plasma biomarkers as a tool to define inflammatory state leads to net inflation of the number of "inflammatory" diseases - an effect that shows clearly in the field of nephrology.

BackgroundThe antidiuretic hormone (ADH) or arginine vasopressin (AVP) regulates the body's water balance. Recently, modifications in AVP levels have been related to osteoporosis during ageing and microgravity/bed rest. Therefore the present study was devised to assess whether the absence of AVP, as in patients with central diabetes insipidus (CDI), modulates renal calcium excretion.MethodsWe retrospectively analysed data from 12 patients with CDI with measured 24-h urinary excretion levels of calcium. Data were available at the moment of the diagnosis when patients were drug-free and after therapy with dDAVP, an analog of AVP. Hypercalciuria was defined as 24-h urinary Ca2+ >275 mg/day in males and >250 mg/day in females and a urinary calcium (Ca):creatinine (Cr) ratio >0.20 mg/mg.ResultsUntreated CDI patients had a daily urinary Ca2+ excretion of 383 ± 47 mg/day and a urinary Ca:Cr ratio of 0.26 ± 0.38 mg/mg. The urine osmolarity significantly increased after the administration of dDAVP by 210% and the urinary flow decreased by 72%. Furthermore, the estimated glomerular filtration rate (eGFR) increased by 7%, which did not reach statistical significance. dDAVP treatment did not significantly modify the urinary Ca2+ concentration; however, the daily calcium excretion and the urinary Ca:Cr ratio were significantly decreased (160 ± 27 mg/day and 0.11 ± 0.02 mg/mg, respectively).ConclusionsPatients with CDI show hypercalciuria even though urine is more diluted than normal controls, and dDAVP reverses this effect. These data support the intriguing relationship between AVP and osteoporosis in ageing and microgravity/bed rest.

Onco-nephrology is an emerging field in medicine. Patients with cancer may suffer from kidney diseases because of the cancer itself and cancer-related therapy. It is critical for nephrologists to be knowledgeable of cancer biology and therapy in order to be fully integrated in the multidisciplinary team and optimally manage patients with cancer and kidney diseases. In a recent international meeting, the key issues in this challenging clinical interface were addressed, including many unresolved basic science questions, such as the high tumor incidence in kidney transplant recipients. To this end, 70 highly qualified faculty members were gathered from all over the world to discuss these issues in 8 plenary sessions, including 5 keynote lectures. In addition, 48 young nephrologists and oncologists were invited to present their original observations that were highlighted in 2 large poster sessions.

Chronic kidney disease (CKD) is now seen as a systemic disease involving also the central nervous system [1], but the link between the kidney and different organ systems and disease went unnoticed for a long time. The king of Poland, Stephen Bathory (1533-86), suffered from CKD due to polycystic kidney disease and depression [2]. Similarly, Wolfgang Amadeus Mozart was also thought to have had CKD [3] and depression [4]. A list of 'Famous People Who Have Died from Kidney Disease' [5] includes many who suffered from both CKD and depression or other signs of mental illness. Is this a coincidence or actually evidence of a link between kidney disease and brain dysfunction? This is not merely an academic question because all forms of mental illness can seriously impair an individual's quality of life, and are frequently associated with progression of diseases and premature mortality, so it is worth the effort of trying to answer it. Europe and much of the industrialized countries are experiencing growing numbers of patients with CKD within their ageing populations [6]. CKD is complex and potentially fatal: (i) all organs are affected, sooner or later; (ii) the balance of plasma volume, electrolytes, acid-base and minerals, metabolites, hormones and proteins is disturbed; and (iii) patients often need a multidisciplinary team approach managing complex comorbidities, drug regimens and special diets. Although the prognosis of patients with CKD remains poor, their increasing life expectancy has shifted medical attention from life-threatening emergencies to long-term complications and sequelae, and how to improve quality of life [7]. Indeed, kidney failure has detrimental effects on health-related quality of life (HRQoL), reaching levels similar to those seen in patients with metastatic cancer [8]. This might be due to psychological factors, both kidney disease and cancer being chronic diseases with a bad prognosis. However, although the effect of CKD on quality of life is more evident in advanced stages (stage G4P) and in older patients [9, 10], a large study has shown a significant decrease in HRQoL as early as CKD stage G2 [11]. Notably, neurological and cognitive impairments [12], and depression [13] are among the most debilitating consequences of CKD contributing to the significantly reduced HRQoL [14].

Purpose: The purpose of this study was to report the clinical and functional results of a series of patients with early knee osteoarthritis (KOA) treated with the intra-articular injection of autologous adipose-derived stem cells (aASCs) plus arthroscopic debridement. The hypothesis was that protocol would significantly improve the clinical and functional outcomes in patients with early KOA. Methods: Fifty-two patients with early KOA, who received arthroscopic debridement followed by percutaneous injection of aASCs, were enrolled into the study and retrospectively analyzed with an average follow-up of 15.3 (range, 6 to 24) months. Patients were assessed through the IKS knee and function scores and VAS pain scale. Results: The mean IKS knee score improved from 37.4 (range, 14 to 79) points pre-operatively to 62.6 (range, 27 to 95) points at the latest follow-up (p < < 0.01). The mean IKS function score improved from 57.2 (range, 25 to 100) points pre-operatively to 83.0 (range, 35 to 100) points at the latest follow-up (p < < 0.01). The mean VAS score decreased from 8.5 (range, 3 to 10) pre-operatively to 5.1 (range, 0 to 8) at the latest follow-up (p < < 0.01). Additionally, patients with a pre-operative VAS score greater than 8 were found to show greater clinical and functional benefits compared with patients with VAS score lower than 8. Conclusions: The knee injection of aASCs associated to arthroscopic debridement increased significantly the clinical and functional scores in patients with early KOA at a mid-term follow-up, especially those with higher pre-operative VAS scores.

BackgroundThe 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.MethodsThis 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 (r).ResultsThe total number of nephrons inversely correlated with the systolic blood pressure (r= −0.4,p< 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) (r= 0.62,p< 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.DiscussionThe 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.

Aim: Different factors have been hypothesized to play a role in the cascade of events associated with the protein-induced glomerular response. However, scant data are available on the possible functional effect of vasopressin (VP) on the glomerular filtration rate (GFR) in humans with central diabetes insipidus (CDI), which was the aim of the present study. Method: Renal function was studied under fasting conditions (baseline) and after a meat meal in 16 patients with CDI before and after treatment with desmopressin (DDAVP) and in 16 control subjects. GFR was measured by the inulin method. Results: At baseline, the GFR was lower in patients with CDI. Treatment with DDAVP resulted in an insignificant increase in GFR, which was not statistically different from untreated patients. After an acute oral protein load, the GFR increased, peaking at 45min post meal in controls, and at 135min post meal in treated and untreated CDI patients. Conclusion: After a meat meal, the peak GFR response is delayed in CDI patients suggesting that VP might indirectly affect tubule-glomerular feedback.

Cyclic movements, such as walking/cycling, require the activity of spinal-circuits, the central-pattern-generators (CPG). To our knowledge little work has been done to investigate the activation of these circuits, e.g., the muscular and kinematic activity during cycling initiation. This study aims to detail the muscle output properties as a function of the initial lower limb-position using a simple cycling paradigm. Therefore, subjects were required to pedal on a cycle-ergometer in seated position starting at different-crank-angles (0–150°). Surface-electromyography was recorded from the gluteus major (GL), vastus lateralis (VL), and gastrocnemius medialis (GM), while crank position was recorded using a linear-encoder. Gluteus major peak-activity (PA) occurred at 65.0±12.4° when starting with 0° initial crank position (ICP), while occurred maximally at 110.5±2.9 when starting with 70° ICP. Vastus lateralis PA occurred at 40.7±8.8° with 0° ICP, whereas with 70° ICP PA occurred at 103.4±4.0°. Similarly, GM PA occurred at 112.0±10.7° with 0° ICP, whereas with 70° ICP PA occurred at 142.5±4.2° PA. Gluteus major and gastrocnemius medialis showed similar PA phase shifts, which may suggest they are controlled by same local circuitry, in agreement with their common spinal origin, i.e., motoneurons pool in S1–S2.

The relationship between genes and anxious behavior, is nor linear nor monotonic. To address this problem, we analyzed with a meta-analytic method the literature data of the behavior of knockout mice, retrieving 33 genes whose deletion was accompanied by increased anxious behavior, 34 genes related to decreased anxious behavior and 48 genes not involved in anxiety. We correlated the anxious behavior resulting from the deletion of these genes to their brain expression, using the Allen Brain Atlas and Gene Expression Omnibus (GEO) database. The main finding is that the genes accompanied, after deletion, by a modification of the anxious behavior, have lower expression in the cerebral cortex, the amygdala and the ventral striatum. The lower expression level was putatively due to their selective presence in a neuronal subpopulation. This difference was replicated also using a database of human gene expression, further showing that the differential expression pertained, in humans, a temporal window of young postnatal age (4 months up to 4 years) but was not evident at fetal or adult human stages. Finally, using gene enrichment analysis we also show that presynaptic genes are involved in the emergence of anxiety and postsynaptic genes in the reduction of anxiety after gene deletion.

Spatial memory deficits are a common hallmark of psychiatric conditions, possibly due to a genetic predisposition. Thus, unravelling the relationship between genes and memory might suggest novel therapeutic targets and pathogenetic pathways. Genetic deletions are known to lead to memory deficits (post-deletion "forgetfulness" genes, PDF), or, in few instances to improve spatial memory (post-deletion "hypermnesic" genes, PDH). To assess this topic, we performed a meta-analytic approach on memory behavior in knock-out mice. We screened 300 studies from PubMed and retrieved 87 genes tested for possible effects on spatial memory. This database was crossed with the Allen Brain Atlas (brain distribution) and the Enrichr (gene function) databases. The results show that PDF genes have higher expression level in several ventral brain structures, particularly the encephalic trunk and in the hypothalamus. Moreover, part of these genes are implicated in synaptic functions. Conversely, the PDH genes are associated to G-protein coupled receptors downstream signalling. Some candidate drugs were also found to interfere with some of the PDH genes, further suggesting that this approach might help in identifying drugs to improve memory performance in psychiatric conditions.

The uncoupling protein-2 (UCP2) is an anion transporter that plays a key role in the control of intracellular oxidative stress. In animal models UCP2 downregulation has several pathological sequelae, particularly affecting the vasculature and the kidney. Specifically, in these models kidney damage is highly favored in the absence of UCP2 in the context of experimental hypertension. Confirmations of these data in humans awaits further information, as no data are yet available concerning the cell-type and subcellular expression in the human kidney. In the present study, we aimed to characterize the UCP2 protein distribution in human kidney biopsies. In humans UCP2 is mainly localized in proximal convoluted tubule cells, with an intracytoplasmic punctate staining. UCP2 positive puncta are often localized at the interface between the endoplasmic reticulum and the mitochondria. Glomerular structures do not express UCP2 at detectable levels. The expression of UCP2 in proximal tubular cells may explain their relative propensity to damage in pathological conditions including the hypertensive disease.

In the last decades, proteomics has been largely applied to the Nephrology field, with the double aim to (1) elucidate the biological processes underlying renal diseases; (2) identify disease-specific biomarkers, predictor factors of therapeutic efficacy and prognostic factors of disease progression. Kidney stone disease, and in particular, inherited nephrolithiasis (INL) are not an exception. Given the multifactorial origin of these disorders, the combination of genomics and proteomics studies may complement each other, with the final objective to give a global and comprehensive mechanistic view. In this review, we summarize the results of recent proteomic studies which have expanded our knowledge about INL, focusing the attention on monogenic forms of nephrolithiasis (cystinuria, Dent’s disease, Bartter syndrome, distal renal tubular acidosis and primary hyperoxaluria), on polygenic hypercalciuria and on medullary sponge kidney disease.

Background The classical approach to the analysis of kidney biopsies is based on semi-quantitative scores of the amount of sclerosis, inflammatory infiltrate, fibrosis and vascular damage. However, advanced renal lesions may be accompanied by a paucity of clinical features and, conversely, important clinical abnormalities may be accompanied by minimal histopathological changes. The objective of this study is to correlate new, semiautomatic, quantitative features of kidney biopsies (e.g. fractal analysis) with clinical and hematological parameters using a cross-sectional design. Methods Whole slide images from sixty-seven biopsies of patients diagnosed for diabetic nephropathy, hypertensive nephropathy, focal segmental glomerulosclerosis (FSGS) or IgA nephropathy have been used. The images have been semi-automatically quantified in the ImageJ environment, in order to derive the glomerular density, the tubular density, the number of tubules per glomerulus and the fractal dimension of the tubular lumen in the cortex (an index of complexity of the tubular lumen). For each patient, hemato-chemical data have been retrieved, including the uric acid level and the creatinine-based eGFR. Results A linear relationship between eGFR and glomerular density was observed in hypertension and FSGS, but not in diabetic nephropathy. Conversely, the eGFR correlated with the tubular density across different glomerular conditions. Moreover, the tubular density was linearly correlated with uric acid levels in different pathological conditions. The fractal dimension of tubular lumen was correlated with the eGFR but only in hypertensive patients. Finally, blood pressure was not correlated to any of the morphological indices tested. Conclusions We propose the use of the fractal dimension as a new morphological descriptor of the nephron integrity.