ELISPOT assays with pp65 peptides or whole HCMV antigen are reliable predictors of immune control of HCMV infection in seropositive kidney transplant recipients.

Human cytomegalovirus (HCMV) infection represents a major complication for solid organ transplant recipients. The aim of this study was to verify if the measurement of HCMV-specific T-cells could help to identify patients protected against HCMV disease cytokine flow cytometry using infected dendritic cells as stimulus (CFC-iDC, which discriminates between CD4+ and CD8+ T cells), and ELISPOT, using infected cell lysate (ELISPOT-iCL) or pp65 (ELISPOT-pp65) as stimulus, were adopted. Among the 47 kidney transplant recipients (KTR) enrolled, 29 had a self-resolving HCMV infection (Controllers) and 18 required antiviral treatment (Non-Controllers). HCMV-specific T-cell frequency at the peak of HCMV infection identified Controllers and Non-Controllers, although the diagnostic performance of CD8+ CFC-iDC (area under the curve [AUC] of the receiver-operator characteristic curve: 0.65) was lower than that of CD4+ CFC-iDC (AUC: 0.83), ELISPOT-iCL (AUC: 0.83) and ELISPOT-pp65 (AUC: 0.80). CFC-iDC detected a protective immune reconstitution significantly earlier (median time: 38 days) than ELISPOT-iCL and ELISPOT-pp65 (median time: 126 and 133 days, respectively). Time to protective immune reconstitution in Non-Controllers was significantly longer than in Controllers with the ELISPOT and the CD4+ CFC-iDC assays, but not with CD8+ CFC-iDC. The majority of patients did not require antiviral treatment after protective immune reconstitution, with the exception of five patients according to CFC-iDC assay, one patient according to ELISPOT-iCL assay and three patients according to ELISPOT-pp65 assay. Monitoring the HCMV-specific immunological reconstitution with is effective in discriminating KTR at risk of or protected from HCMV disease and the ELISPOT assays are suitable for implementation in the clinical setting.

SARS-CoV-2-specific IgG and NCP in vulnerable patients without symptoms.

Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS- CoV-2-specific IgG than patients with mild symptoms. In this retrospective study we considered different categories of patients defined as "vulnerable" because affected by other pathologies, such as patients with genetic and cardiovascular diseases; patients with autoimmune dermatological dis- ease; kidney and lung transplant patients, and pregnant women because the prevalence of Covid-19 infection during pregnancy is not known. This study was performed at IRCCS San Matteo Hospital in Pavia, North Italy, a zone considered at high risk during the COVID-19 pandemic from June to December 2020. None of the positive screened patients had symptoms of COVID-19 infection at the time of inclusion in this study.

Liposome Formulation and In Vitro Testing in Non-Physiological Conditions Addressed to Ex Vivo Kidney Perfusion.

This work focuses on formulating liposomes to be used in isolated kidney dynamic machine perfusion in hypothermic conditions as drug delivery systems to improve preservation of transplantable organs. The need mainly arises from use of kidneys from marginal donors for transplantation that are more exposed to ischemic/reperfusion injury compared to those from standard donors. Two liposome preparation techniques, thin film hydration and microfluidic techniques, are explored for formulating liposomes loaded with two model proteins, myoglobin and bovine serum albumin. The protein-loaded liposomes are characterized for their size by DLS and morphology by TEM. Protein releases from the liposomes are tested in PERF-GEN perfusion fluid, 4 °C, and compared to the in vitro protein release in PBS, 37 °C. Fluorescent liposome uptake is analyzed by fluorescent microscope in vitro on epithelial tubular renal cell cultures and ex vivo on isolated pig kidney in hypothermic perfusion conditions. The results show that microfluidics are a superior technique for obtaining reproducible spherical liposomes with suitable size below 200 nm. Protein encapsulation efficiency is affected by its molecular weight and isoelectric point. Lowering incubation temperature slows down the proteins release; the perfusion fluid significantly affects the release of proteins sensitive to ionic media (such as BSA). Liposomes are taken up by epithelial tubular renal cells in two hours' incubation time.

CD73-Adenosinergic Axis Mediates the Protective Effect of Extracellular Vesicles Derived from Mesenchymal Stromal Cells on Ischemic Renal Damage in a Rat Model of Donation after Circulatory Death.

We propose a new organ-conditioning strategy based on mesenchymal stromal cell (MSCs)/extracellular vesicle (EVs) delivery during hypothermic perfusion. MSCs/EVs marker CD73 is present on renal proximal tubular cells, and it protects against renal ischemia-reperfusion injury by converting adenosine monophosphate into adenosine (ADO). In this study, after checking if CD73-silenced EVs (EVsi) would impact in vitro tubular-cell proliferation, we perfused kidneys of a rat model of donation after circulatory death, with Belzer solution (BS) alone, BS supplemented with MSCs, EVs, or EVsi. The ADO and ATP levels were measured in the effluents and tissues. Global renal ischemic damage score (GRS), and tubular cell proliferation index (IPT) were evaluated in the tissue. EVsi did not induce cell proliferation in vitro. Ex vivo kidneys perfused with BS or BS + EVsi showed the worst GRS and higher effluent ADO levels than the MSC- and EV-perfused kidneys. In the EV-perfused kidneys, the tissue and effluent ATP levels and IPT were the highest, but not if CD73 was silenced. Tissue ATP content was positively correlated with tissue ADO content and negatively correlated with effluent ADO level in all groups. In conclusion, kidney conditioning with EVs protects against ischemic damage by activating the CD73/ADO system.

Kidney Transplants From Donors on Extracorporeal Membrane Oxygenation Prior to Death Are Associated With Better Long-Term Renal Function Compared to Donors After Circulatory Death.

Donation after circulatory death (DCD) allows expansion of the donor pool. We report on 11 years of Italian experience by comparing the outcome of grafts from DCD and extracorporeal membrane oxygenation (ECMO) prior to death donation (EPD), a new donor category. We studied 58 kidney recipients from DCD or EPD and collected donor/recipient clinical characteristics. Primary non function (PNF) and delayed graft function (DGF) rates, dialysis need, hospitalization duration, and patient and graft survival rates were compared. The estimated glomerular filtration rate (eGFR) was measured throughout the follow-up. Better clinical outcomes were achieved with EPD than with DCD despite similar graft and patient survival rates The total warm ischemia time (WIT) was longer in the DCD group than in the EPD group. Pure WIT was the highest in the class II group. The DGF rate was higher in the DCD group than in the EPD group. PNF rate was similar in the groups. Dialysis need was the greatest and hospitalization the longest in the class II DCD group. eGFR was lower in the class II DCD group than in the EPD group. Our results indicate good clinical outcomes of kidney transplants from DCD despite the long "no-touch period" and show that ECMO in the procurement phase improves graft outcome, suggesting EPD as a source for pool expansion.

Hemoperfusion with CytoSorb as Adjuvant Therapy in Critically Ill Patients with SARS-CoV2 Pneumonia.

We report a preliminary experience of adjuvant therapy with Hemoperfusion (HP) in patients with Severe Acute Respiratory Syndrome-CoronaVirus 2 (SARS-CoV2) pneumonia. Currently, there are no approved treatments for CoronaVirus Disease 19 (COVID-19); however, therapeutic strategies based on the preclinical evidence include supportive measures, such as oxygen supplementation, antiviral, and anticoagulant agents. Despite these treatments, 10% of patients worsen and develop severe acute respiratory distress syndrome (ARDS). Since the pathogenic mechanism of ARDS is an uncontrolled inflammatory state, we speculate that removing inflammation effectors from blood may contrast tissue injury and improve clinical outcome. In a scenario of dramatic medical emergency, we conducted an observational study on 9 consecutive patients hospitalized in COVID Intensive Care Unit, where 5 of 9 consecutive patients were treated with HP, due to the emergency overload made it impossible to deliver blood purification in the other 4 patients. COVID-19 was diagnosed through the identification of virus sequences by reverse transcription-PCR on respiratory specimens. All patients had severe pneumonia requiring continuous positive airway pressure. HP was started in all patients 6-7 days after hospital admission. The treated patients (T) received 2 consecutive sessions of HP using CytoSorb cartridge. Our results show a better clinical course of T compared to control patients (C), in fact all T except 1 survived, and only 2 of them were intubated, while all C required intubation and died. Lymphocytopenia worsened in C but not in T. C-reactive protein decreased in both patients, but to a greater extent in T. IL-6, IL-8, and TNF-α decreased after HP, IL-10 did not change. Respiratory function remained stable and did not worsen in T compared to C. The limited sample size and observational study design preclude a sound statement about the potential effectiveness of HP in COVID-19 patients, but our experience suggests a potential therapeutic role of adjuvant CytoSorb HP in the early course of CO-VID-19 pneumonia. A randomized clinical trial is ongoing.

Kidney transplant rejection rate in screened patients for anti-SARS-CoV-2 antibodies, during COVID-19 pandemic in Northern Italy.

Coronavirus is a high-risk pathogen for kidney transplant recipients receiving immunosuppressive therapy; Coronavirus disease 2019 (COVID-19) is an infection causing severe acute respiratory syndrome (SARS-CoV2), and progressive withdrawal of immunosuppressive drugs has been suggested in transplanted patients. At IRCCS San Matteo Hospital in Pavia, Northern Italy, during the pandemic we performed a screening and all transplanted patients were evaluated for IgG anti SARS-CoV-2; 12 of 201 kidney transplant recipients (6%) screened for IgG anti SARS-CoV-2 (s) developed kidney transplant rejection; 10 (83%) were negative and 2 (17%) resulted positive for SARS-CoV-2 IgG, while among 189 patients without rejection, 162 (86%) resulted negative and 27 (14%) positive (P=0.69). COVID 19 course may be more severe in kidney transplant recipients but it does not significantly increase risk of kidney rejection.

Vitamin e-loaded membrane dialyzers reduce hemodialysis inflammaging.

BACKGROUND: Inflammaging is a persistent, low-grade, sterile, nonresolving inflammatory state, associated with the senescence of the immune system. Such condition downregulates both innate and adaptive immune responses during chronic disorders as type II diabetes, cancer and hemodialysis, accounting for their susceptibility to infections, malignancy and resistance to vaccination. Aim of this study was to investigate hemodialysis inflammaging, by evaluating changes of several hemodialysis treatments on indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation. METHODS: We conducted a randomized controlled observational crossover trial. Eighteen hemodialysis patients were treated with 3 different hemodialysis procedures respectively: 1) Low-flux bicarbonate hemodialysis, 2) Low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, and 3) Hemodialfitration. The control group consisted of 14 hospital staff healthy volunteers. Blood samples were collected from all 18 hemodialysis patients just after the long interdialytic interval, at the end of each hemodialysis treatment period. RESULTS: Hemodialysis kynurenine and kynurenine/L - tryptophan blood ratio levels were significantly higher, when compared to the control group, indicating an increased indoleamine 2,3-dioxygenase-1 activity in hemodialysis patients. At the end of the low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers period, L - tryptophan serum levels remained unchanged vs both low-flux bicarbonate hemodialysis and hemodialfitration. Kynurenine levels instead decreased, resulting in a significant reduction of kynurenine/L - tryptophan blood ratio and indoleamine 2,3-dioxygenase-1 activity, when matched to both low-flux bicarbonate hemodialysis and HDF respectively. Serum nitric oxide control group levels, were significantly lower when compared to all hemodialysis patient groups. Interestingly, low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers nitric oxide serum levels from venous line blood samples taken 60 min after starting the hemodialysis session were significantly lower vs serum taken simultaneously from the arterial blood line. CONCLUSIONS: The treatment with more biocompatible hemodialysis procedure as low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers, reduced indoleamine 2,3-dioxygenase-1 activity and nitric oxide formation when compared to both low-flux bicarbonate hemodialysis and hemodialfitration. These data suggest that low-flux bicarbonate hemodialysis with vitamin E - loaded dialyzers lowering hemodialysis inflammaging, could be associated to changes of proinflammatory signalling a regulated molecular level. TRIAL REGISTRATION: NCT Number: NCT02981992; Other Study ID Numbers: 20100014090. First submitted: November 26, 2016. First posted: December 5, 2016. Last Update Posted: December 5, 2016.

Significance of serum Myostatin in hemodialysis patients.

BACKGROUND: Malnutrition and muscle wasting are common in haemodialysis (HD) patients. Their pathogenesis is complex and involves many molecules including Myostatin (Mstn), which acts as a negative regulator of skeletal muscle. The characterisation of Mstn as a biomarker of malnutrition could be useful in the prevention and management of this condition. Previous studies have reported no conclusive results on the actual relationship between serum Mstn and wasting and malnutrition. So, in this study, we evaluated Mstn profile in a cohort of regular HD patients. METHODS: We performed a cross-sectional study, enrolling 37 patients undergoing bicarbonate-HD (BHD) or haemodiafiltration (HDF) at least for six months. 20 sex-matched healthy subjects comprised the control group. Mstn serum levels were evaluated by ELISA before and after HD. We collected clinical and biochemical data, evaluated insulin resistance, body composition, malnutrition [by Malnutrition Inflammation Score (MIS)] and tested muscle function (by hand-grip strength, six-minute walking test and a questionnaire on fatigue). RESULTS: Mstn levels were not significantly different between HD patients and controls (4.7 ± 2.8 vs 4.5 ± 1.3 ng/ml). In addition, while a decrease in Mstn was observed after HD treatment, there were no differences between BHD and HDF. In whole group of HD patients Mstn was positively correlated with muscle mass (r = 0.82, p < 0.001) and inversely correlated with age (r = - 0.63, p < 0.01) and MIS (r = - 0.39, p = 0.01). No correlations were found between Mstn and insulin resistance, such as between Mstn levels and parameters of muscle strength and fatigue. In multivariate analysis, Mstn resulted inversely correlated with fat body content (ß = - 1.055, p = 0.002). CONCLUSIONS: Circulating Mstn is related to muscle mass and nutritional status in HD patients, suggesting that it may have a role in the regulation of skeletal muscle and metabolic processes. However, also considering the lack of difference of serum Mstn between healthy controls and HD patients and the absence of correlations with muscle function tests, our findings do not support the use of circulating Mstn as a biomarker of muscle wasting and malnutrition in HD.

Early onset of graft glomerulopathy in a patient with post-transplant diabetes mellitus after renal transplantation: a case report.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is an emerging problem in kidney transplantation, representing an important risk factor for kidney function loss. Diabetic nephropathy (DN) occurrence in transplanted kidneys is poorly investigated. Current knowledge describes DN recurrence in graft 5.9 years from kidney transplantation however there is little data about PTDM and DN. Here, we report a clinical case peculiar for an early appearance of advanced glomerular diabetic lesions, after kidney transplantation. CASE PRESENTATION: A 45-year-old Caucasian male affected by autosomal polycystic kidney disease was transplanted with a cadaveric-kidney-donor from 58-year-old male. Induction immunosuppressive therapy included basiliximab and steroids while the maintenance treatment included, tacrolimus, mofetil micophenolate and methylprednisolone. One month after transplantation the patient developed diabetes requiring treatment with repaglinide quickly replaced with insulin to obtain an acceptable glycemic control (HbA1c 52 mmol/mol). Glycosuria was detected persistently during the first six months after transplantation. To achieve further improvement in glycemic control, a shift from tacrolimus to cyclosporine (CyA) was made and steroids were rapidly tapered and stopped. To minimize calcineurin inhibitors toxicity, which was revealed in the 1-year-protocol-biopsy, everolimus was introduced thereby lowering CyA through levels. Moderate hypertension was well controlled with doxazosin. Thirty months after transplantation a second graft biopsy was performed owing to renal function decline and microalbuminuria appearance. Histological analysis surprisingly showed mesangiolysis and microaneurysms; glomerular sclero-hyalinosis and basal membrane thickness and typical nodular glomerulosclerosis. C4d staining was negative and no evidence of immune deposits were detected. Donor Specific Antibodies, serum C3 and C4 levels and autoimmunity tests were negative. Retrospective analysis on donor history didn't show diabetes or insulin resistance and no diabetic lesions were found in kidney pre-implant biopsy. CONCLUSIONS: In our knowledge, this is the first report describing a very early onset of advanced diabetic glomerular lesions in a graft biopsy after PTDM. We hypothesize that additional factors such as everolimus and hypertension, may have contribute to kidney damage.

Soluble Toll-like Receptor 4: A New Player in Subclinical Inflammation and Malnutrition in Hemodialysis Patients.

OBJECTIVE: Toll-like receptor 4 (TLR4) promotes inflammation in hemodialysis patients (HD). A soluble form of extracellular TLR4 (sTLR4) has been recently characterized, which showed the ability to attenuate TLR4 signalling. In this study, we describe the sTLR4 profile in regular HD patients. SUBJECTS: In a cross-sectional study we enrolled forty prevalent HD patients (68.2 ± 16.3 years, twenty-five males) with a median dialysis vintage of 41 months. Nineteen patients were undergoing standard bicarbonate HD (BHD) and 21 patients on-line hemodiafiltration (HDF). Ten healthy sex-matched subjects constituted the controls (C). INTERVENTION: Before and after the HD session, serum was tested for sTLR4 levels by ELISA. Moreover, clinical and biochemical data were collected, including body mass index, albumin, and C-reactive protein (CRP) levels. Body composition was expressed as a 3-compartment model, providing lean tissue index and fat tissue index (FTI). MAIN OUTCOME MEASURE: Describe the profile of sTLR4 in HD patients, evaluating the correlations among sTLR4 levels and the main clinical characteristics, inflammatory and nutritional parameters. RESULTS: Patients with subclinical inflammation (i.e., high CRP levels without clinical symptomatology) presented higher sTLR4 levels (0.42 ± 0.25 ng/mL) with respect to both C and not inflamed HD patients (0.23 ± 0.19 ng/mL, P < .05). There was a significant direct correlation between predialysis sTLR4 and body mass index, FTI (r = 0.55), and CRP levels (r = 0.52) and inverse correlation with lean tissue index and albumin (r = -0.4). In multivariate analysis, sTLR4 resulted directly associated with FTI (P = .038). Notably, sTLR4 levels resulted higher in bicarbonate hemodialysis versus hemodiafiltration (0.37 ± 0.18 vs. 0.19 ± 0.21 ng/mL, P < .05). CONCLUSIONS: sTLR4 correlates with inflammatory and nutritional parameters, presenting as a new potential player in modulating subclinical inflammation in HD patients.

Perfusion of isolated rat kidney with Mesenchymal Stromal Cells/Extracellular Vesicles prevents ischaemic injury.

Kidney donation after circulatory death (DCD) is a less than ideal option to meet organ shortages. Hypothermic machine perfusion (HMP) with Belzer solution (BS) improves the viability of DCD kidneys, although the graft clinical course remains critical. Mesenchymal stromal cells (MSC) promote tissue repair by releasing extracellular vesicles (EV). We evaluated whether delivering MSC-/MSC-derived EV during HMP protects rat DCD kidneys from ischaemic injury and investigated the underlying pathogenic mechanisms. Warm ischaemic isolated kidneys were cold-perfused (4 hrs) with BS, BS supplemented with MSC or EV. Renal damage was evaluated by histology and renal gene expression by microarray analysis, RT-PCR. Malondialdehyde, lactate, LDH, glucose and pyruvate were measured in the effluent fluid. MSC-/EV-treated kidneys showed significantly less global ischaemic damage. In the MSC/EV groups, there was up-regulation of three genes encoding enzymes known to improve cell energy metabolism and three genes encoding proteins involved in ion membrane transport. In the effluent fluid, lactate, LDH, MDA and glucose were significantly lower and pyruvate higher in MSC/EV kidneys as compared with BS, suggesting the larger use of energy substrates by MSC/EV kidneys. The addition of MSC/EV to BS during HMP protects the kidney from ischaemic injury by preserving the enzymatic machinery essential for cell viability and protects the kidney from reperfusion damage.

Hepatocyte growth factor (HGF) and hemodialysis: physiopathology and clinical implications.

Hepatocyte growth factor (HGF) is a pleiotropic cytokine which exerts a variety of effects on several cells, being involved in the regulation of many biological processes, such as inflammation, tissue repair, morphogenesis, angiogenesis, tumour propagation, immunomodulation of viral infections and cardio-metabolic activities. Patients undergoing regular hemodialysis (HD) present elevated levels of HGF, mainly due to the leukocyte activation associated with HD treatment. High HGF levels might account for specific clinical features of HD patients, i.e. mild liver damage in course of HCV-infection and high cardiovascular risk profile. Moreover, in patients with acute kidney injury, the induction of HGF may represent a crucial step to promote renal recovery, which can have important prognostic consequences in the short and long-term. In this review we discuss the mechanisms underlying HGF production in HD patients, the role of HGF in this particular patient population and the potential clinical implications derived from the study of HGF in HD patients.

Mesenchymal stromal cells reset the scatter factor system and cytokine network in experimental kidney transplantation.

BACKGROUND: In former studies we showed in a rat model of renal transplantation that Mesenchymal Stromal Cells (MSC) prevent acute rejection in an independent way of their endowing in the graft. In this study we investigated whether MSC operate by resetting cytokine network and Scatter Factor systems, i.e. Hepatocyte Growth Factor (HGF), Macrophage Stimulating Protein (MSP) and their receptors Met and RON, respectively. METHODS: MSC were injected into the renal artery soon after reperfusion. Controls were grafted untreated and normal rats. Rats were sacrificed 7 days after grafting. Serum and renal tissue levels of IFN-γ, IL-1, IL-2, IL-4, IL-6, IL-10, MSP/RON, HGF/Met systems, Treg lymphocytes were investigated. RESULTS: In grafted untreated rats IFN-γ increased in serum and renal tissue and IL-6 rose in serum. MSC prevented both the phenomena, increased IL-10 serum levels and Treg number in the graft. Furthermore MSC increased serum and tissue HGF levels, Met tubular expression and prevented the suppression of tubular MSP/RON expression. CONCLUSIONS: Our results demonstrate that MSC modify cytokine network to a tolerogenic setting, they suppress Th1 cells, inactivate monocytes/macrophage, recruit Tregs. In addition, MSC sustain the expression of the Scatter Factor systems expression, i.e. systems that are committed to defend survival and stimulate regeneration of tubular cells.

Yet another in vitro evidence that natural compounds introduced by diet have anti-amyloidogenic activities and can counteract neurodegenerative disease depending on aging.

A major issue in Alzheimer's disease (AD) research is to find some new therapeutic drug which decrease Amyloid-beta (Aß) aggregation. From a therapeutic point of view the major question is whether pharmacological inhibition of inflammation pathways will be able to safely reverse or slow the course of disease. Natural compounds are capable of binding to different targets implicated in AD and exert neuroprotective effects. Aim of this study was to evaluate the in vitro inhibition of Aß1-42 fibrillogenesis in presence of Gallic acid, Rutin, Melatonin and ProvinolsTM . We performed the analysis with Transmission and Scanning Electron Microscopy, and with X-ray microanalysis. Samples treated with Rutin, that arises from phenylalanine via the phenylpropanoid pathway, show the best effective result obtained because a significantly fibril inhibition activity is detectable compared to the other compounds. Melatonin shows a better inhibitory activity than ProvinolsTM and Gallic acid at the considered concentrations.

Renal diseases in haemophilic patients: pathogenesis and clinical management.

Haemophilia A and B are genetic X-linked bleeding disorders, caused by mutations in genes encoding factors VIII and IX, respectively. Clinical manifestations of haemophilia are spontaneous haemorrhage or acute bleeding caused by minor trauma, resulting in severe functional consequences that can culminate in a debilitating arthropathy. Life expectancy and quality of life of patients with haemophilia have dramatically improved over the last years, mainly for new therapeutic options and the awareness to the risk of HCV and HIV infections. Different clinical problems arise from this important change in history of patients with haemophilia. In particular, ageing-related diseases, such as diabetes, hypertension and cancer, and chronic viral infections are emerging as new challenges in this patient population. Among the different types of chronic illnesses, renal diseases are of special interest as they involve some difficult management issues. In fact, decisions regarding adequate preventive strategies and viral infection treatment, the choice of the dialytic modality, placement of vascular access and prescription of dialytic treatments are particularly complicated, because only few data are available. In this review, we discuss the pathogenesis of renal damage in patients with haemophilia, especially in those with blood-transmitted viral infections, and the major issues about the management of renal diseases, including problems related to dialytic treatment and kidney transplantation, providing practical algorithms to guide the clinical decision-making process.

A retrospective analysis of dermatological lesions in kidney transplant patients.

BACKGROUND & OBJECTIVES: Kidney transplantation is the best option for patients with end-stage renal disease (ESRD) failure. Prolonged use of immunosuppressive drugs often causes opportunistic infections and malignancies of skin and mucosae, but due to lack of a careful dermatological screening in several transplantation centers the diagnosis and the treatment of dermatological lesions in kidney transplant patients are underestimated. In addition after the introduction of interleukin (IL)-2 -receptor antagonists (basiliximab/daclizumab), mTOR inhibitors and mycophenolate mofetil (MMF)/mycophenolic acid (MPA) in new immunosuppressive protocols only a few studies have analyzed the skin and mucosal lesions in kidney transplant patients. This study was undertaken to evaluate the cutaneous and mucosal diseases after kidney transplantation, and to investigate the association between these and different immunosuppressive protocols and/or demographic features. METHODS: A retrospective analysis was done using medical records of kidney transplantation between 2000 and 2009 at the Transplant Unit of Fondazione IRCCS Policlinico San Matteo, Pavia, Italy. The study included 183 patients (M 57.3%, F 42.7%) aged 51.5 ± 11.8 yr) with transplant age 52.3 ± 34.9 months. Induction therapy was basiliximab and steroids based; maintenance therapy included combination-regimes from cyclosporine, tacrolimus, steroids, mycophenolate mofetil (MM), mycophenolic acid (MPA), rapamycin, everolimus. Anti-rejection therapy was steroid and/or thymoglobulines based. Diagnosis of cutaneous disease was made through examination of skin, mucous membranes, nails and hair evaluation. Skin biopsies, specific cultures and serological tests were done when required. RESULTS: Skin and mucosal diseases were reported in 173 (95.7%) of patients; 88 (50.81%) showed viral lesions; 92 (53.01%) immunosuppression-related lesions; 28 (16.39%) benign tumours; 26 (15.3%) precancers /neoplastic lesions; 24 (14.21%) mycosis; 16 (9.29%) cutaneous xerosis, 15 (8.74%) dermatitis, while absence of cutaneous disease was evident only in 8 (4.37%) cases. An association between drug side effects and anti-rejection treatment ( P ≤ 0.01) and/or calcineurin-inhibitors (CNI) exposure ( P ≤ 0.01) was found. Longer exposure to immunosuppressive drugs (>60 months) was associated with pre-malignancy and malignancy lesions. INTERPRETATION & CONCLUSIONS: Cutaneous diseases are frequent in kidney transplanted patients. Continuous skin monitoring is necessary to make an early diagnosis and to start appropriate treatment.

Multiple electrolyte disorders in a neurosurgical patient: solving the rebus.

BACKGROUND: It is important to ensure an adequate sodium and volume balance in neurosurgical patients in order to avoid the worsening of brain injury.Indeed, hyponatremia and polyuria, that are frequent in this patient population, are potentially harmful, especially if not promptly recognized.Differential diagnosis is often challenging, including disorders, which, in view of similar clinical pictures, present very different pathophysiological bases, such as syndrome of inappropriate antidiuresis, cerebral/renal salt wasting syndrome and diabetes insipidus. CASE PRESENTATION: Here we present the clinical report of a 67-year-old man with a recent episode of acute subarachnoid haemorrhage, admitted to our ward because of severe hyponatremia, hypokalemia and huge polyuria.We performed a complete workup to identify the underlying causes of these alterations and found a complex picture of salt wasting syndrome associated to primary polydipsia. The appropriate diagnosis allowed us to correct the patient hydro-electrolyte balance. CONCLUSION: The comprehension of the pathophysiological mechanisms is essential to adequately recognize and treat hydro-electrolyte disorders, also solving the most complex clinical problems.

Mechanisms underlying sCD40 production in hemodialysis patients.

CD40 and its ligand (CD40L) regulate several cellular functions, including T and B-cell activation. The soluble form of CD40 (sCD40) antagonizes CD40/CD40L interaction. Patients undergoing hemodialysis (HD) present elevated sCD40 serum levels, which underlying molecular mechanisms are unknown. We studied sCD40 serum and urinary levels, CD40 membrane and gene expression and membrane shedding in HD, uremic not-HD patients (UR) and healthy subjects (N). We found that in HD sCD40 serum levels were higher than UR and N, being significantly elevated in anuric patients, and that sCD40 correlated to renal function in UR subjects, who presented also a reduced sCD40 urinary excretion rate. HD and UR presented reduced CD40 membrane and gene expression. The concentration of TNF-α converting enzyme (TACE), responsible for CD40 cleavage was not different between HD and N. Therefore the reduced renal clearance is the main cause of elevated sCD40 levels in HD. This finding could have relevant clinical implications.