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Hypertension is one of the major health problems leading to the development of cardiovascular diseases. Despite a rapid expansion in global hypertension prevalence, molecular mechanisms leading to hypertension are not fully understood largely due to the complexity of pathogenesis involving several factors. Salt intake is recognized as a leading determinant of blood pressure, since reduced dietary salt intake is related to lower morbidity and mortality, and hypertension in relation to cardiovascular events. Compared with salt-resistant populations, salt-sensitive individuals exhibit high sensitivity in blood pressure responses according to changes in salt intake. In this setting, the kidney plays a major role in the maintenance of blood pressure under the hormonal control of the renin–angiotensin–aldosterone system. In the present review, we summarize the current overview on the molecular mechanisms for modulation of blood pressure associated with renal ion channels/transporters including sodium–hydrogen exchanger isoform 3 (NHE3), Na+-K+-2Cl– cotransporter (NKCC2), sodium–chloride cotransporter (NCC), epithelial sodium channel (ENaC) and pendrin expressed in different nephron segments. In particular, recent studies on experimental animal models with deletion of renal ion channels led to the identification of several crucial physiological mechanisms and molecules involved in hypertension. These findings could further provide a potential for novel therapeutic approaches applicable on human patients with hypertension.

BACKGROUND: Mutations in SLC37A4, which encodes the intracellular glucose transporter G6PT, cause the rare glycogen storage disease type 1b (GSD1b). A long-term consequence of GSD1b is kidney failure, which requires KRT. The main protein markers of proximal tubule function, including NaPi2A, NHE3, SGLT2, GLUT2, and AQP1, are downregulated as part of the disease phenotype.METHODS: We utilized an inducible mouse model of GSD1b, TM-G6PT-/-, to show that glycogen accumulation plays a crucial role in altering proximal tubule morphology and function. To limit glucose entry into proximal tubule cells and thus to prevent glycogen accumulation, we administered an SGLT2-inhibitor, dapagliflozin, to TM-G6PT-/- mice.RESULTS: In proximal tubule cells, G6PT suppression stimulates the upregulation and activity of hexokinase-I, which increases availability of the reabsorbed glucose for intracellular metabolism. Dapagliflozin prevented glycogen accumulation and improved kidney morphology by promoting a metabolic switch from glycogen synthesis toward lysis and by restoring expression levels of the main proximal tubule functional markers.CONCLUSION: We provide proof of concept for the efficacy of dapagliflozin in preserving kidney function in GSD1b mice. Our findings could represent the basis for repurposing this drug to treat patients with GSD1b.

Background The kidney is the main organ in the pathophysiology of essential hypertension. Although most bicarbonate reabsorption occurs in the proximal tubule, the medullary thick ascending limb (mTAL) of the nephron also maintains acid–base balance by contributing to 25% of bicarbonate reabsorption. A crucial element in this regulation is the sodium-hydrogen exchanger 1 (NHE1), a ubiquitous membrane protein controlling intracellular pH, where proton extrusion is driven by the inward sodium flux. MicroRNA (miRNA) expression of hypertensive patients significantly differs from that of normotensive subjects. The aim of this study was to determine the functional role of miRNA alterations at the mTAL level. Methods By miRNA microarray analysis, we identified miRNA expression profiles in isolated mTALs from high sodium intake–induced hypertensive rats (HSD) versus their normotensive counterparts (NSD). In vitro validation was carried out in rat mTAL cells. Results Five miRNAs involved in the onset of salt-sensitive hypertension were identified, including miR-23a, which was bioinformatically predicted to target NHE1 mRNA. Data demonstrated that miRNA-23a is downregulated in the mTAL of HSD rats while NHE1 is upregulated. Consistently, transfection of an miRNA-23a mimic in an mTAL cell line, using a viral vector, resulted in NHE1 downregulation. Conclusion NHE1, a protein involved in sodium reabsorption at the mTAL level and blood pressure regulation, is upregulated in our model. This was due to a downregulation of miRNA-23a. Expression levels of this miRNA are influenced by high sodium intake in the mTALs of rats. The downregulation of miRNA-23a in humans affected by essential hypertension corroborate our data and point to the potential role of miRNA-23a in the regulation of mTAL function following high salt intake.

Renal micropuncture, which requires the direct access to the renal tubules, has for long time been the technique of choice to measure the single nephron glomerular filtration rate (SNGFR) in animal models. This approach is challenging by virtue of complex animal preparation and numerous technically difficult steps. The introduction of intravital multiphoton microscopy (MPM) offers another approach to the measure of the SNGFR by mean of the high laser-tissue penetration and the optical sectioning capacity. Previous MPM studies measuring SNGFR in vivo relied on fast full-frame acquisition during the filtration process obtainable with high performance resonant scanners. In this study, we describe an innovative linescan–based MPM method. The new method can discriminate SNGFR variations both in conditions of low and high glomerular filtration, and shows results comparable to conventional micropuncture both for rats and mice. Moreover, this novel approach has improved spatial and time resolution and is faster than previous methods, thus enabling the investigation of SNGFR from more tubules and improving options for data-analysis.

Medical societies have a social responsibility to disseminate knowledge and inform health authorities on threats to public health posed by various diseases. Advocacy for health protection programmes and for medical research funding is now embedded into the missions of most scientific societies. To promote kidney research funding in Europe, the European Renal Association – European Dialysis and Transplant Association (ERA-EDTA), rather than acting as an individual society advocating for the fight against kidney disease, has actively helped to create an alliance of national associations centred on kidney diseases, the European Kidney Health Alliance (EKHA), and joined the Biomedical Alliance (BMA). The ERA-EDTA is fully committed to supporting its working groups (WGs) and consortia of its members to allow them to produce valuable kidney research. The framing and formalization of projects, and the regulatory issues related to submission to the European Commission, are complex. To help WGs to gain expert advice from agencies with specific know-how, the ERA-EDTA has adopted a competitive approach. The best research projects proposed by WGs and consortia of other European investigators will receive seed funding to cover the costs of consultancy by expert agencies. Via its broader platforms, the EKHA and the BMA, the ERA-EDTA will strive towards broader recognition of kidney disease and related clusters of non-communicable diseases, by European and national agencies, as major threats to the qualities of life of their populations and their economies.

Thyroid cancers require complex and heterogeneous therapies with different impacts on renal function. In our systematic literature review, we analyzed several aspects: renal function assessment, the impact of radiotherapy and thyroid surgery on kidney functioning, and mechanisms of nephrotoxicity of different chemotherapy, targeted and immunologic drugs. Our study revealed that the renal impact of thyroid cancer therapy can be a limiting factor in all radiotherapy, surgery, and pharmacological approaches. It is advisable to conduct a careful nephrological follow-up imposing the application of body surface based estimated Glomerular Filtration Rate (eGFR) formulas for the purpose of an early diagnosis and treatment of renal failure, guaranteeing the therapy continuation to thyroid cancer patients.

Metabolic acidosis, defined as a plasma or serum bicarbonate concentration, Graphical Abstract Graphical Abstract

Bardet–Biedl syndrome (BBS) is a rare autosomal recessive ciliopathy resulting in multiple organ dysfunctions, including chronic kidney disease (CKD). Despite the recent progress in the ’ciliopathy’ field, there is still little information on the mechanisms underlying renal disease. To elucidate these pathomechanisms, we conducted a translational study, including (i) the characterization of the urine metabolomic pattern of BBS patients and controls in a pilot and confirmation study and (ii) the proteomic analysis of the BBS10 interactome, one of the major mutated BBS genes in patients, in a renal-epithelial-derived cell culture model. The urine metabolomic fingerprinting of BBS patients differed from controls in both pilot and confirmation studies, demonstrating an increased urinary excretion of several monocarboxylates, including lactic acid (LA), at both early and late CKD stages. Increased urine LA was detected in the absence of both increased plasmatic LA levels and generalized proximal tubular dysfunction, suggesting a possible renal-specific defective handling. The inner medulla renal epithelial (IMCD3) cell line, where Bbs10 was stably invalidated, displayed an increased proliferative rate, increased ATP production, and an up-regulation of aerobic glycolysis. A mass spectrometry-based analysis detected several putative BBS10 interactors in vitro, indicating a potential role of BBS10 in several biological processes, including renal metabolism, RNA processing, and cell proliferation. The present study suggests that the urine metabolomic pattern of BBS patients may reflect intra-renal metabolic aberrations. The analysis of BBS10 interactors unveils possible novel functions, including cell metabolism.

EAST/SeSAME syndrome is a rare disease affecting the Central Nervous System (CNS), inner ear, and kidney. The syndrome is due to loss-of-function mutations in the KCNJ10 gene encoding the inward-rectifying potassium channel Kir4.1. EAST/SeSAME syndrome is mainly diagnosed during childhood with a tonic-clonic seizure being the usual first symptom. Due to a limited number of patients and recent identification of the disease, few data are available on the clinical progress of this disease in adulthood. In particular, neurologic and nephrological outcomes have not been reported. We present a case series of 4 adult patients harbouring homozygous missense mutation p.Ala167Val and homozygous frameshift mutations p.Asn232Glnfs*14 and p.Gly275Valfs*7. Effects of these mutations were predicted by in silico modelling and bioinformatic tools. Patients with truncating mutations were associated with more severe outcomes, both in tubulopathy severity and neurological symptomatology. Conversely, either missense or truncating mutations were correlated with similar severity of epilepsy, with a long free-of-event period up to 20 years old. No eGFR decline was documented. Modelling predicted that truncating mutations lead to complete Kir4.1 dysfunction. Finally, all patients had a mild increase in urinary protein excretion. Our study indicates that the prognosis of patients suffering from EAST/SeSAME syndrome is related to the severity of the mutation causing the disease. As predicted by in silico modelling, truncating mutations of KCNJ10 are associated with more severe disease, with recurrence of symptomatic hypokalemia and more severe neurological phenotype. The type of mutation should be considered for the therapy tailored to patients' phenotype.

Background: Hypertension is a complex disease and is the major cause of cardiovascular complications. In the vast majority of individuals, the aetiology of elevated blood pressure (BP) cannot be determined, thus impairing optimized therapies and prognosis for individual patients. A more precise understanding of the molecular pathogenesis of hypertension remains a pressing priority for both basic and translational research. Here we investigated the effect of salt on naive hypertensive patients in order to better understand the salt intake-blood pressure relationship. Methods: Patients underwent an acute saline infusion and were defined as salt-sensitive or salt-resistant according to mean blood pressure changes. Urinary proteome changes during the salt load test were analysed by a label-free quantitative proteomics approach. Results: Our data show that salt-sensitive patients display equal sodium reabsorption as salt-resistant patients, as major sodium transporters show the same behaviour during the salt load. However, salt-sensitive patients regulate the renin angiotensin system (RAS) differently from salt-resistant patients, and upregulate proteins, as epidermal growth factor (EGF) and plasminogen activator, urokinase (PLAU), involved in the regulation of epithelial sodium channel ENaC activity. Conclusions: Salt-sensitive and salt-resistant subjects have similar response to a saline/volume infusion as detected by urinary proteome. However, we identified glutamyl aminopeptidase (ENPEP), PLAU, EGF and Xaa-Pro aminopeptidase 2 precursor XPNPEP2 as key molecules of salt-sensitivity, through modulation of ENaC-dependent sodium reabsorption along the distal tubule. Graphic abstract: [Figure not available: see fulltext.].

BACKGROUND AND AIMS Peritoneal dialysis (PD) is a renal replacement therapy that allows the elimination of metabolic waste products and excess body fluid through the peritoneal membrane. The exposure to PD solution contributes to membrane aging and fibrosis resulting in ultrafiltration and clearance failure. The glucose, used as an osmotic factor, in PD dialysate triggers several processes involved in the pathogenesis of peritoneal fibrosis, angiogenesis and epithelial to mesenchymal transition. Studies on natural extracts, such as Oleuropein (Ole), a powerful antioxidant with remarkable antifibrotic and protective effects on the peritoneal membrane, are currently being validated. This study aims to develop a method based on multi-photon microscopy to study the physiology of the peritoneal membrane during dialysis exchange and to validate in vivo the effects of the Ole in animal models of fibrosis undergoing dialysis treatment. METHOD Multi-photon microscopy allows in vivo evaluation of the microcirculation that supply the peritoneum and also to study the framework of mesothelial cells and their underlying layer of collagen fibers that contributes to the sub-mesothelial space. We have implemented the surgical procedure in order to optimize the stability of a flap of parietal peritoneum to directly observe at the scope. With this approach the peritoneal membrane is evaluable at baseline condition and during exposure to dialysate solutions. RESULTS Our method allows building a three-dimensional render of the peritoneal membrane, with the evaluation of all the single layers without the use of specific markers. In this way we could assess specifically the phenomena induced by the fibrotic process: the thickening of the sub-mesothelial interstitium and the greater density of the vascular network. Furthermore, in vivo measurements of flow in the vessels of microcirculation (arterioles, capillaries, post-capillary venules) determine that exposure to hypotonic solutions increases significantly the flow in large-diameter vessels due to better permeability and hemodilution. Finally in order to evaluate the possibility to detect morphological and functional changes in pathogenic model we have used the well-established model of peritoneal fibrosis derived by 15 days’ long exposure of the peritoneal membrane with 3.86% glucose dialysate. Whth this approach we could detect the significant increase in the parameters of cellularity, vascularization, fibrosis and thickening of collagen fibers. In order to test the sensibility of our approach to the evaluation of the peritoneal membrane senescence parameters, we tested the effect of Ole in preventing the damage induced by high glucose–containing dialysate. Ole reduced both the thickness and the organization of the collagen fibers and the vascular network, including the number of branch points. CONCLUSION The developed method has potential for a dynamic and reliable in vivo approach. Studies are ongoing to validate the effects of drugs and dialysates with different osmotic and electrolytic compositions on the dialysis capacities of the peritoneal membrane and on the blood flow in peritoneal capillaries. This method offers great potential for testing new pharmacological approaches aimed at preserving the structural and functional integrity of the peritoneum and for the validation of substances, such as natural extracts with beneficial effects against the damage induced in the long term by conventional dialysis solutions.

Bardet–Biedl syndrome (BBS) is a rare pleiotropic disorder known as a ciliopathy. Despite significant genetic heterogeneity, BBS1 and BBS10 are responsible for major diagnosis in western countries. It is well established that eight BBS proteins, namely BBS1, 2, 4, 5, 7, 8, 9, and 18, form the BBSome, a multiprotein complex serving as a regulator of ciliary membrane protein composition. Less information is available for BBS6, BBS10, and BBS12, three proteins showing sequence homology with the CCT/TRiC family of group II chaperonins. Even though their chaperonin function is debated, scientific evidence demonstrated that they are required for initial BBSome assembly in vitro. Recent studies suggest that genotype may partially predict clinical outcomes. Indeed, patients carrying truncating mutations in any gene show the most severe phenotype; moreover, mutations in chaperonin-like BBS proteins correlated with severe kidney impairment. This study is a critical review of the literature on genetics, expression level, cellular localization and function of BBS proteins, focusing primarily on the chaperonin-like BBS proteins, and aiming to provide some clues to understand the pathomechanisms of disease in this setting.

Mutations in COL4A3-A5 cause a spectrum of glomerular disorders, including thin basement membrane nephropathy (TBMN) and Alport syndrome (AS). The wide application of next-generation sequencing (NGS) in the last few years has revealed that mutations in these genes are not limited to these clinical entities. In this study, 176 individuals with a clinical diagnosis of inherited kidney disorders underwent an NGS-based analysis to address the underlying cause; those who changed or perfected the clinical diagnosis after molecular analysis were selected. In 5 out of 83 individuals reaching a molecular diagnosis, the genetic result was unexpected: three individuals showed mutations in collagen type IV genes. These patients showed the following clinical pictures: (1) familial focal segmental glomerulosclerosis; (2) end-stage renal disease (ESRD) diagnosed incidentally in a 49-year-old man, with diffuse cortical calcifications on renal imaging; and (3) dysmorphic and asymmetric kidneys with multiple cysts and signs of tubule–interstitial defects. Genetic analysis revealed rare heterozygote/compound heterozygote COL4A4-A5 variants. Our study highlights the key role of NGS in the diagnosis of inherited renal disorders and shows the phenotype variability in patients carrying mutations in collagen type IV genes.

Background Nivolumab is a drug belonging to the class of Immune Checkpoint Inhibitors (ICPI), the use of which has improved the prognosis for patients with various advanced malignancies. These agents are associated with several "immune-mediated" adverse effects, although the literature on Nivolumab renal toxicity is poor and anecdotal. A rare immune-mediated renal adverse event is acute interstitial nephritis (AIN) that often imposes Nivolumab suspension. Case report We present the case of a 75-year-old woman with stage IV melanoma (inguinal and external iliac lymph node metastases without localization of the primitive lesion). At diagnosis, renal function was normal by age (Creatinine 0.89 mg/dl; CKD EPI eGFR 71 ml/min/1.73 m2). After lymphadenectomy, an adjuvant treatment with Nivolumab was initiated. At 4-month follow-up, the patient was hospitalized for AKI (creatinine 2.6 mg/dl; eGFR 17,3 ml/min/1.73 m2). Although, renal function decline was not accompanied by signs of systemic immunoactivation, Nivolumab was suspended. In the following weeks, only a partial renal function recovery was observed, still limiting immunotherapy reintroduction. Thus, the patient was referred to our Onconephrology Outpatient Unit for a multidisciplinary approach. We performed a urinalysis with microscopy study of the sediment and observed rare dysmorphic red blood cells and leukocytes. To exclude a glomerulopathy, a comprehensive screening for autoimmune diseases and 24 hours proteinuria were also measured and found not significant (Table 1). Renal ultrasound did not show any relevant alteration. Based on our original suspicion of AIN, although in absence of an history of fever, rush or eosinophilia, we introduced Prednisone 25 mg/day. In the following weeks, blood and urine tests showed a significant improvement in renal function (serum creatinine 1.06 mg/dL, eGFR CKD-EPI 51 mL/min/1.73m2) and the absence of red blood cells, leukocytes and proteinuria in the urinalysis. Based on nephrologist advice, the patient was then able to resume the cancer treatment with a maintenance dose of prednisone equal to 5 mg/day. Conclusion AIN is a rare adverse effect of ICPIs that mandates the close monitoring of renal function in patients under immunotherapy with these agents. AKI occurrence in patients treated with ICPIs should always lead to investigate a possible AIN, even in the absence of the classic symptom set of fever, rush and eosinophilia and with minimal changes in urinalysis. Based on our single observation, and after an accurate literature review, we suggest the initiation of a corticosteroid treatment in oncologic patients on an ICPI complicated with AKI and with suspicion of AIN at urinalysis. Moreover, this case report thickens the importance of a multidisciplinary approach to oncologic patients not only when a conventional nephrotoxic chemotherapy has to be started, but also in case of ICIPs use. The nephrologist advice, in fact, could be useful in both preventing and treating severe renal complications such as AIN, also allowing the oncologic therapy maintenance.

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 Malignant hypercalcemia is a common complication in cancer patients and can be predictive of poor prognosis and advanced malignancy. Cancer-related mechanisms of hypercalcemia depends either on ectopic hypersecretion of humoral factors (PTH, PTH-like molecules, Vit D) by the tumoral mass, or on osteolysis due to bone invasion. In consideration of the high renal and cardiac impact of severe hypercalcemia, its prompt recognition and treatment can be lifesaving. AKI is frequently associated with malignant hypercalcemia and recognizes a multifactorial pathogenesis (direct renal vasoconstriction, volume depletion, tubule-interstitial damage, etc.). Substitutive renal treatment can be necessary, but not always viable in patients with poor physical performance and is a difficult choice in cancer patients with advanced malignancies. Case report We present the case of a 46 years old woman with an infiltrating non special type (NST) carcinoma of the right breast (luminal B, ER 70%, PgR 60%, Ki67 35%, HER2 1+). Unfortunately, she quickly progressed after a neoadjuvant treatment with Epirubicin/Cyclophosfamide (4 cycles) followed by Paclitaxel (10 cycles). A first line hormonal treatment (Palbociclib, Letrozole and LHRH analogous) was then started, but a further rapid disease progression was observed. A new biopsy showed a muted and more aggressive cancer phenotype (high grade triple negative carcinoma with no PDL1 expression). Due to a rapid worsening of general conditions with cognitive impairment, the patient was admitted to the Oncology department. Blood test showed severe hypercalcemia (corrected calcium: 23.26 mg/dl) and severe hypokalemic metabolic alkalosis (blood pH 7.57; HCO-3 32 mmol/l; K+ 2.6 mmol/l) associated to AKI (creatinine doubled to 1.42 mg/dl; eGFR 45 ml/min/1,73 mq). Alkaline phosphatase and Vitamin D were normal and iPTH was < 2 pg/ml. ECG showed a significant QTc prolongation to 550 msec. Imaging exams revealed lung metastasis, lung carcinomatous lymphangitis and bilateral pleural effusion, while Bone Scan showed a low caption limited to right ribs. Oncologists and Intensive Care Physicians referred to our Nephrology and Dialysis Unit proposing Hemodialysis support. In consideration of the preserved diuresis, the advanced disease stage and the unstable hemodynamics, our advice was instead for a conservative medical approach. An i.v. infusion of 4000 ml NaCl 0.9% + KCl 60 mEq/24h; a continuous i.v. infusion of Furosemide 5mg/h were started and maintained for several days, leading to a progressive and full renal function recovery (creatinine decreased to 0.7 mg/dl) and metabolic alkalosis correction. However, corrected calcium remained largely over target, being 16.3 mg/dl. Sodium bicarbonate 80 mEq, Zoledronic acid 4 mg and Desametasone 4mg/day were administered and at day 16 even calcium was in normal range. We realized that this was a favourable window for acting on the underlaying cause of malignant hypercalcemia, that likely was the aberrant secretion of non-dosable PTH-like molecule(s). Thus, we suggested the Oncologist to start chemotherapy, and they were allowed to treat the patient with Carboplatin/Gemcitabine. The patient was successfully treated with stabilization of normocalcemia and is still alive. Conclusion Malignant hypercalcemia is a life-threatening complication in advanced malignancies. Our case report highlights the key role of the nephrologist in treating a complex and fragile oncologic patient, achieving the full correction of several severe renal disorders, hemodialysis avoidance and survival improvement.

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.